Article first published online:  08 May 2019

Miguel A. Perez-Sousa, Luis Carlos Venegas-Sanabria, Diego Andrés Chavarro-Carvajal, Carlos Alberto Cano-Gutierrez, Mikel Izquierdo, Jorge Enrique Correa-Bautista, Robinson Ramírez-Vélez

Gait speed as a mediator of the effect of sarcopenia on dependency in activities of daily living
Background
Sarcopenia in older adults is strongly associated with an increase in dependency in activities of daily living (ADL) and with a decline in gait speed. Interestingly, gait speed has been shown to independently predict mortality. In this context, our study aimed to explore the mediator role of gait speed on the relationship between sarcopenia and dependency in ADL.
Methods
A cross-sectional study was conducted in Colombia, 19 705 older adults with a mean age of 70 years, 55.6% women, 16.1% with sarcopenia, and 14.7% mild, moderate, or severe dependency in ADL, according to ‘SABE Survey 2015’. Sarcopenia was assessed by calf circumference and ADL dependence through the Barthel Index. Gait speed was measured over a distance of 3 m. The association between sarcopenia condition and gait speed and dependency level was analysed by linear regression adjusted by covariates. To examine whether gait speed mediated the association between sarcopenia and dependence components of physical function, simple mediation models were generated using ordinary least squares with the macro PROCESS version 3.2, adjusted for age, sex, and body mass index (BMI).
Results
Significant differences (P < 0.05) were found in gait speed and dependency in ADL between the sarcopenia and non-sarcopenia groups after adjusting for age, sex, and BMI. BMI was significantly higher in the non-sarcopenia group whereas dependency was significantly higher in the sarcopenia group (19.6% vs. 13.8%). Results from mediation model regression analysis indicated a significant and direct detrimental effect of sarcopenia on dependency in ADL (ß = -0.05; P < 0.001), and a significant indirect effect of gait speed on the direct effect (-0.009 to -0.004).
Conclusions
The negative effect of sarcopenia on functional dependence was mediated by the gait speed. Therefore, gait speed may positively influence the detrimental effect of sarcopenia for dependency, after adjusting for age, gender, and BMI. Consequently, physical exercise should be promoted and focused to circumvent the gait speed decline associated with age in older people with sarcopenia.

Perez-Sousa, M. A., Venegas-Sanabria, L. C., Chavarro-Carvajal, D. A., Cano-Gutierrez, C. A., Izquierdo, M., Correa-Bautista, J. E., and Ramírez-Vélez, R. ( 2019) Gait speed as a mediator of the effect of sarcopenia on dependency in activities of daily living. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12444.

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     Article first published online:  08 May 2019

Patrick J. Owen, Robin M. Daly, Jack Dalla Via, Niamh L. Mundell, Patricia M. Livingston, Timo Rantalainen, Steve F. Fraser

The clinical relevance of adiposity when assessing muscle health in men treated with androgen deprivation for prostate cancer
Background
Androgen deprivation therapy (ADT) for prostate cancer (PCa) may prospectively decrease absolute lean mass (LM) and increase absolute fat mass (FM). Given that estimates of LM by dual-energy X-ray absorptiometry may be overestimated in obese people, this study examined the influence of adiposity on muscle health in men treated with ADT for PCa.
Methods
This cross-sectional study examined the influence of adiposity on total and appendicular LM (ALM), muscle cross-sectional (CSA), and muscle strength in 70 men treated with ADT [mean (standard deviation) age, 71 (6) years] for PCa compared with age-matched PCa (n = 52) and healthy controls (n = 70). Total body LM, FM and ALM, and 66% tibia and radius muscle CSA were quantified by dual-energy X-ray absorptiometry and peripheral quantitative computed tomography, respectively. ALM was further divided by height (m2) or body mass index, with muscle CSA expressed as a per cent of total limb CSA. Upper and lower body and back (three-repetition maximum and dynamometry) muscle strength were expressed per kilogram of body weight.
Results
On average, ADT-treated men had 4.4–6.4 kg greater FM compared with controls (P = 0.014) and there were no differences in total body or ALM. Total body per cent LM and ALMBMI were 3.8–5.4% (P = 0.001) and 7.8–9.4% (P = 0.001) lower, respectively, in ADT-treated men compared with both controls. Percentage muscle CSA at both sites and muscle strength (except leg) were 3.0–6.0% (P = 0.031) and 15–17% (P = 0.010) lower, respectively, in ADT-treated men compared with both controls.
Conclusions
The findings from this study indicate muscle mass, size, and strength are compromised in men treated with ADT after accounting for their increased adiposity or body size.

Owen, P. J., Daly, R. M., Dalla Via, J., Mundell, N. L., Livingston, P. M., Rantalainen, T., and Fraser, S. F. ( 2019) The clinical relevance of adiposity when assessing muscle health in men treated with androgen deprivation for prostate cancer, Journal of Cachexia, Sarcopenia and Muscle, doi: https://doi.org/10.1002/jcsm.12446.

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     Article first published online:  08 May 2019

Arthur Goron, Frédéric Lamarche, Sandrine Blanchet, Pascale Delangle, Uwe Schlattner, Eric Fontaine, Christophe Moinard

Citrulline stimulates muscle protein synthesis, by reallocating ATP consumption to muscle protein synthesis
Background
Animal studies and clinical data support the interest of citrulline as a promising therapeutic for sarcopenia. Citrulline is known to stimulate muscle protein synthesis, but how it affects energy metabolism to support the highly energy-dependent protein synthesis machinery is poorly understood.
Methods
Here, we used myotubes derived from primary culture of mouse myoblasts to study the effect of citrulline on both energy metabolism and protein synthesis under different limiting conditions.
Results
When serum/amino acid deficiency or energy stress (mild uncoupling) were applied, citrulline stimulated muscle protein synthesis by +22% and +11%, respectively. Importantly, this increase was not associated with enhanced energy status (ATP/ADP ratio) or mitochondrial respiration. We further analysed the share of mitochondrial respiration and thus of generated ATP allocated to different metabolic pathways by using specific inhibitors. Our results indicate that addition of citrulline allocated an increased share of mitochondrially generated ATP to the protein synthesis machinery under conditions of both serum/amino acid deficiency (+28%) and energy stress (+21%). This reallocation was not because of reduced ATP supply to DNA synthesis or activities of sodium and calcium cycling ion pumps.
Conclusions
Under certain stress conditions, citrulline increases muscle protein synthesis by specifically reallocating mitochondrial fuel to the protein synthesis machinery. Because ATP/ADP ratios and thus Gibbs free energy of ATP hydrolysis remained globally constant, this reallocation may be linked to decreased activation energies of one or several ATP (and GTP)-consuming reactions involved in muscle protein synthesis.

Goron, A., Lamarche, F., Blanchet, S., Delangle, P., Schlattner, U., Fontaine, E., and Moinard, C. ( 2019) Citrulline stimulates muscle protein synthesis, by reallocating ATP consumption to muscle protein synthesis. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12435.

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     Article first published online:  07 May 2019

Pradeep Harish, Alberto Malerba, Ngoc Lu-Nguyen, Leysa Forrest, Ornella Cappellari, Fanny Roth, Capucine Trollet, Linda Popplewell, George Dickson

Inhibition of myostatin improves muscle atrophy in oculopharyngeal muscular dystrophy (OPMD)
Background
Oculopharyngeal muscular dystrophy (OPMD) is a late-onset muscle disease affecting one per 80 000 of the general population characterized by profound dysphagia and ptosis, and limb weakness at later stages. Affected muscles are characterized by increased fibrosis and atrophy. Myostatin is a negative regulator of muscle mass, and inhibition of myostatin has been demonstrated to ameliorate symptoms in dystrophic muscles.
Methods
In this study, we performed a systemic delivery of a monoclonal antibody to immunologically block myostatin in the A17 mouse model of OPMD. The mice were administered a weekly dose of 10 mg/kg RK35 intraperitonially for 10 weeks, following which histological analyses were performed on the samples.
Results
This treatment significantly (P < 0.01) improved body mass (11%) and muscle mass (for the tibialis anterior and extensor digitorum longus by 19% and 41%) in the A17 mice treated with RK35 when compared to saline controls. Similarly, a significantly (P < 0.01) increased muscle strength (18% increase in maximal tetanic force) and myofibre diameter (17% and 44% for the tibialis anterior and extensor digitorum longus), and reduced expression of markers of muscle fibrosis (40% reduction in area of expression), was also observed. No change in the density of intranuclear inclusions (a hallmark of disease progression of OPMD) was however observed.
Conclusions
Our study supports the clinical translation of such antibody-mediated inhibition of myostatin as a treatment of OPMD. This strategy has implications to be used as adjuvant therapies with gene therapy based approaches, or to stabilize the muscle prior to myoblast transplantation.

Harish, P., Malerba, A., Lu-Nguyen, N., Forrest, L., Cappellari, O., Roth, F., Trollet, C., Popplewell, L., and Dickson, G. ( 2019) Inhibition of myostatin improves muscle atrophy in oculopharyngeal muscular dystrophy (OPMD). Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12438.

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     Article first published online:  03 May 2019

Douglas W. Gould, Emma L. Watson, Thomas J. Wilkinson, Joanne Wormleighton, Soteris Xenophontos, Joao L. Viana

Ultrasound assessment of muscle mass in response to exercise training in chronic kidney disease: a comparison with MRI
Background
Chronic kidney disease (CKD) is a catabolic condition associated with muscle wasting and dysfunction, which associates with morbidity and mortality. There is a need for simple techniques capable of monitoring changes in muscle size with disease progression and in response to interventions aiming to increase muscle mass and function. Ultrasound is one such technique; however, it is unknown how well changes in muscle cross-sectional area (CSA) measured using ultrasound relate to changes in whole muscle volume measured using magnetic resonance imaging. We tested whether rectus femoris CSA (RF-CSA) could be used as a valid indication of changes in quadriceps muscle volume as a single measure of muscle size and following a 12 week exercise intervention that resulted in muscle hypertrophy.
Methods
Secondary analysis of data was collected from the ExTra CKD study (ISRCTN 36489137). Quadriceps muscle size was assessed from 36 patients with non-dialysis CKD before and after 12 weeks of supervised exercise that resulted in muscle hypertrophy.
Results
Strong positive correlations were observed between RF-CSA and quadriceps volume at baseline (r2 = 0.815, CI 0.661 to 0.903; P < 0.001) and following 12 week exercise (r2 = 0.845, CI 0.700 to 0.923; P < 0.001). A moderate positive association was also observed between changes in RF-CSA and quadriceps following exercise training (rho = 0.441, CI 0.085 to 0.697; P = 0.015). Bland–Altman analysis revealed a small bias (bias 0.6% ± 12.5) between the mean percentage changes in RF-CSA and quadriceps volume but wide limits of agreement from -24 to 25.
Conclusions
Rectus femoris CSA appears to be a reliable index of total quadriceps volume as a simple measure of muscle size, both as a single observation and in response to exercise training in non-dialysis CKD patients.

Gould, D. W., Watson, E. L., Wilkinson, T. J., Wormleighton, J., Xenophontos, S., Viana, J. L., and Smith, A. C. ( 2019) Ultrasound assessment of muscle mass in response to exercise training in chronic kidney disease: a comparison with MRI. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12429.

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     Article first published online:  29 April 2019

Daniel I. Brierley, Joe R. Harman, Natasha Giallourou, Emma Leishman, Anna Emily Roashan, Ben A.D. Mellows, Heather B. Bradshaw, Jonathan R. Swann, Ketan Patel, Benjamin J. Whalley, Claire M. Williams

Chemotherapy-induced cachexia dysregulates hypothalamic and systemic lipoamines and is attenuated by cannabigerol
Background
Muscle wasting, anorexia, and metabolic dysregulation are common side-effects of cytotoxic chemotherapy, having a dose-limiting effect on treatment efficacy, and compromising quality of life and mortality. Extracts of Cannabis sativa, and analogues of the major phytocannabinoid ?9-tetrahydrocannabinol, have been used to ameliorate chemotherapy-induced appetite loss and nausea for decades. However, psychoactive side-effects limit their clinical utility, and they have little efficacy against weight loss. We recently established that the non-psychoactive phytocannabinoid cannabigerol (CBG) stimulates appetite in healthy rats, without neuromotor side-effects. The present study assessed whether CBG attenuates anorexia and/or other cachectic effects induced by the broad-spectrum chemotherapy agent cisplatin.
Methods
An acute cachectic phenotype was induced in adult male Lister-hooded rats by 6 mg/kg (i.p.) cisplatin. In total 66 rats were randomly allocated to groups receiving vehicle only, cisplatin only, or cisplatin and 60 or 120 mg/kg CBG (po, b.i.d.). Feeding behavior, bodyweight and locomotor activity were recorded for 72 hours, at which point rats were sacrificed for post-mortem analyses. Myofibre atrophy, protein synthesis and autophagy dysregulation were assessed in skeletal muscle, plasma metabolic profiles were obtained by untargeted 1H-NMR metabonomics, and levels of endocannabinoid-like lipoamines quantified in plasma and hypothalami by targeted HPLC-MS/MS lipidomics.
Results
CBG (120 mg/kg) modestly increased food intake, predominantly at 36-60hrs (p<0.05), and robustly attenuated cisplatin-induced weight loss from 6.3% to 2.6% at 72hrs (p<0.01). Cisplatin-induced skeletal muscle atrophy was associated with elevated plasma corticosterone (3.7 vs 13.1ng/ml, p<0.01), observed selectively in MHC type IIx (p<0.05) and IIb (p<0.0005) fibres, and was reversed by pharmacological rescue of dysregulated Akt/S6-mediated protein synthesis and autophagy processes. Plasma metabonomic analysis revealed cisplatin administration produced a wide-ranging aberrant metabolic phenotype (Q2Y=0.5380, p=0.001), involving alterations to glucose, amino acid, choline and lipid metabolism, citrate cycle, gut microbiome function, and nephrotoxicity, which were partially normalized by CBG treatment (Q2Y=0.2345, p=0.01). Lipidomic analysis of hypothalami and plasma revealed extensive cisplatin-induced dysregulation of central and peripheral lipoamines (29/79 and 11/26 screened, respectively), including reversible elevations in systemic N-acyl glycine concentrations which were negatively associated with the anti-cachectic effects of CBG treatment.
Conclusions
Endocannabinoid-like lipoamines may have hitherto unrecognized roles in the metabolic side-effects associated with chemotherapy, with the N-acyl glycine subfamily in particular identified as a potential therapeutic target and/or biomarker of anabolic interventions. CBG-based treatments may represent a novel therapeutic option for chemotherapy-induced cachexia, warranting investigation in tumour-bearing cachexia models.

Brierley, D. I., Harman, J. R., Giallourou, N., Leishman, E., Roashan, A. E., Mellows, B. A. D., Bradshaw, H. B., Swann, J. R., Patel, K., Whalley, B. J., and Williams, C. M. ( 2019) Chemotherapy-induced cachexia dysregulates hypothalamic and systemic lipoamines and is attenuated by cannabigerol. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12426.

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     Article first published online:  29 April 2019

Seung Bae Yoon, Moon Hyung Choi, Meiying Song, Ju Hyun Lee, In Seok Lee, Myung Ah. Lee, Tae Ho Hong, Eun Sun Jung, Myung-Gyu Choi

Impact of preoperative body compositions on survival following resection of biliary tract cancer
Background
Although surgical resection is the only potentially curative treatment for biliary tract cancer, the prognosis remains poor after a major operation such as pancreatoduodenectomy or hepatectomy. We aimed to investigate the impact of preoperative body compositions on long-term survival of patients undergoing resection of biliary tract cancer.
Methods
We analysed data of patients diagnosed with biliary tract cancer who underwent surgery from 2009 to 2015. Skeletal muscle area, skeletal muscle radiation attenuation, and visceral and subcutaneous adipose tissue areas were measured from the computed tomography images at L3 vertebral levels obtained before resection of cancer. Patients were divided into two groups based on the sex-specific median values for each parameter, and long-term survival was compared between the groups.
Results
A total of 371 patients (women, 39.6%; mean age, 66.2 ± 9.6 years) were finally included in the analysis. Patients with low skeletal muscle index (SMI) had significantly shorter median survival than those with high SMI (29 vs. 39 months; P = 0.026). Patients with low skeletal muscle attenuation (SMA) also showed reduced survival compared with those with high SMA (median survival 25 vs. 60 months; P = 0.002). Combining these two factors, survival was highest in the high SMI/high SMA group (reference) and lowest in the low SMI/low SMA group (hazard ratio, 2.18; 95% confidence interval, 1.44–3.30). Visceral and subcutaneous adipose tissue areas were not associated with long-term survival.
Conclusions
Low SMI and low SMA on computed tomography scan have a negative impact on survival after resection of biliary tract cancer. They can be used in preoperative risk assessment to assist in treatment decision making.

Yoon, S. B., Choi, M. H., Song, M., Lee, J. H., Lee, I. S., Lee, M. A., Hong, T. H., Jung, E. S., and Choi, M.-G. ( 2019) Impact of preoperative body compositions on survival following resection of biliary tract cancer. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12431.

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     Article first published online:  24 April 2019

Savina Apolloni, Susanna Amadio, Paola Fabbrizio, Giovanna Morello, Antonio Gianmaria Spampinato, Emanuele Claudio Latagliata, Illari Salvatori, Daisy Proietti, Alberto Ferri, Luca Madaro, Stefano Puglisi-Allegra, Sebastiano Cavallaro, Cinzia Volonté

Histaminergic transmission slows progression of amyotrophic lateral sclerosis
Background
Histamine is an immune modulator, neuroprotective, and remyelinating agent, beneficially acting on skeletal muscles and promoting anti-inflammatory features in amyotrophic lateral sclerosis (ALS) microglia. Drugs potentiating the endogenous release of histamine are in trial for neurological diseases, with a role not systematically investigated in ALS. Here, we examine histamine pathway associations in ALS patients and the efficacy of a histamine-mediated therapeutic strategy in ALS mice.
Methods
We adopted an integrative multi-omics approach combining gene expression profiles, copy number variants, and single nucleotide polymorphisms of ALS patients. We treated superoxide dismutase 1 (SOD1)-G93A mice that recapitulate key ALS features, with the brain-permeable histamine precursor histidine in the symptomatic phase of the disease and analysed the rescue from disease pathological signs. We examined the action of histamine in cultured SOD1-G93A motor neuron-like cells.
Results
We identified 13 histamine-related genes deregulated in the spinal cord of two ALS patient subgroups, among which genes involved in histamine metabolism, receptors, transport, and secretion. Some histamine-related genes overlapped with genomic regions disrupted by DNA copy number and with ALS-linked pathogenic variants. Histidine treatment in SOD1-G93A mice proved broad efficacy in ameliorating ALS features, among which most importantly lifespan, motor performance, microgliosis, muscle atrophy, and motor neurons survival in vivo and in vitro.
Conclusions
Our gene set/pathway enrichment analyses and preclinical studies started at the onset of symptoms establish that histamine-related genes are modifiers in ALS, supporting their role as candidate biomarkers and therapeutic targets. We disclose a novel important role for histamine in the characterization of the multi-gene network responsible for ALS and, furthermore, in the drug development process.

Apolloni, S., Amadio, S., Fabbrizio, P., Morello, G., Spampinato, A. G., Latagliata, E. C., Salvatori, I., Proietti, D., Ferri, A., Madaro, L., Puglisi-Allegra, S., Cavallaro, S., and Volonté, C. ( 2019) Histaminergic transmission slows progression of amyotrophic lateral sclerosis. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12422.

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     Article first published online:  24 April 2019

Yeonhee Hong, Jong Han Lee, Kwang Won Jeong, Cheol Soo Choi, Hee-Sook Jun

Amelioration of muscle wasting by glucagon-like peptide-1 receptor agonist in muscle atrophy
Background
Skeletal muscle atrophy is defined as a reduction of muscle mass caused by excessive protein degradation. However, the development of therapeutic interventions is still in an early stage. Although glucagon-like peptide-1 receptor (GLP-1R) agonists, such as exendin-4 (Ex-4) and dulaglutide, are widely used for the treatment of diabetes, their effects on muscle pathology are unknown. In this study, we investigated the therapeutic potential of GLP-1R agonist for muscle wasting and the mechanisms involved.
Methods
Mouse C2C12 myotubes were used to evaluate the in vitro effects of Ex-4 in the presence or absence of dexamethasone (Dex) on the regulation of the expression of muscle atrophic factors and the underlying mechanisms using various pharmacological inhibitors. In addition, we investigated the in vivo therapeutic effect of Ex-4 in a Dex-induced mouse muscle atrophy model (20 mg/kg/day i.p.) followed by injection of Ex-4 (100 ng/day i.p.) for 12 days and chronic kidney disease (CKD)-induced muscle atrophy model. Furthermore, we evaluated the effect of a long-acting GLP-1R agonist by treatment of dulaglutide (1 mg/kg/week s.c.) for 3 weeks, in DBA/2J-mdx mice, a Duchenne muscular dystrophy model.
Results
Ex-4 suppressed the expression of myostatin (MSTN) and muscle atrophic factors such as F-box only protein 32 (atrogin-1) and muscle RING-finger protein-1 (MuRF-1) in Dex-treated C2C12 myotubes. The suppression effect was via protein kinase A and protein kinase B signalling pathways through GLP-1R. In addition, Ex-4 treatment inhibited glucocorticoid receptor (GR) translocation by up-regulating the proteins of GR inhibitory complexes. In a Dex-induced muscle atrophy model, Ex-4 ameliorated muscle atrophy by suppressing muscle atrophic factors and enhancing myogenic factors (MyoG and MyoD), leading to increased muscle mass and function. In the CKD muscle atrophy model, Ex-4 also increased muscle mass, myofiber size, and muscle function. In addition, treatment with a long-acting GLP-1R agonist, dulaglutide, recovered muscle mass and function in DBA/2J-mdx mice.
Conclusions
GLP-1R agonists ameliorate muscle wasting by suppressing MSTN and muscle atrophic factors and enhancing myogenic factors through GLP-1R-mediated signalling pathways. These novel findings suggest that activating GLP-1R signalling may be useful for the treatment of atrophy-related muscular diseases.

Hong, Y., Lee, J. H., Jeong, K. W., Choi, C. S., and Jun, H.-S. ( 2019) Amelioration of muscle wasting by glucagon-like peptide-1 receptor agonist in muscle atrophy. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12434.

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     Article first published online:  23 April 2019

Leocadio Rodriguez-Mañas, Olga Laosa, Bruno Vellas, Giuseppe Paolisso, Eva Topinkova, Juan Oliva-Moreno, Isabelle Bourdel-Marchasson, Mikel Izquierdo, Kerry Hood, Andrej Zeyfang, Giovanni Gambassi, Mirko Petrovic, Tim C. Hardman, Mark J. Kelson, Ivan Bautmans, Gabor Abellan, Michelangela Barbieri, Luz M. Peña-Longobardo, Sophie C. Regueme, Riccardo Calvani, Stefanie De Buyser, Alan J. Sinclair on behalf of the European MID-Frail Consortium

Effectiveness of a multimodal intervention in functionally impaired older people with type 2 diabetes mellitus
Background
Type 2 diabetes, a highly prevalent chronic disease, is associated with increasing frailty and functional decline in older people. We aimed to evaluate the effectiveness of a multimodal intervention on functional performance in frail and pre-frail participants aged =70 years with type 2 diabetes mellitus.
Methods
The MID-Frail study was a cluster-randomized multicenter clinical trial conducted in 74 trial sites across seven European countries. The trial recruited 964 participants who were aged >70 years [mean age in intervention group, 78.4 (SD 5.6) years, 49.2% male and 77.6 (SD 5.29) years, 52.4% male in usual care group], with type diabetes mellitus and determined to be frail or pre-frail using Fried's frailty phenotype. Participants were allocated by trial site to follow either usual care (UCG) or intervention procedures (IG). Intervention group participants received a multimodal intervention composed of (i) an individualized and progressive resistance exercise programme for 16 weeks; (ii) a structured diabetes and nutritional educational programme over seven sessions; and (iii) Investigator-linked training to ensure optimal diabetes care. Short Physical Performance Battery (SPPB) scores were used to assess change in functional performance at 12 months between the groups. An analysis of the cost-effectiveness of the intervention was undertaken using the incremental cost-effectiveness ratio (ICER). Secondary outcomes included mortality, hospitalization, institutionalization, quality of life, burden on caregivers, the frequency and severity of hypoglycaemia episodes, and the cost-effectiveness of the intervention.
Results
After 12 months, IG participants had mean SPPB scores 0.85 points higher than those in the UCG (95% CI, 0.44 to 1.26, P < 0.0001). Dropouts were higher in frail participants and in the intervention group, but significant differences in SPPB between treatment groups remained consistent after sensitivity analysis. Estimates suggest a mean saving following intervention of 428.02 EUR (2016) per patient per year, with ICER analysis indicating a consistent benefit of the described health care intervention over usual care. No statistically significant differences between groups were detected in any of the other secondary outcomes.
Conclusions
We have demonstrated that a 12 month structured multimodal intervention programme across several clinical settings in different European countries leads to a clinically relevant and cost-effective improvement in the functional status of older frail and pre-frail participants with type 2 diabetes mellitus.

Rodriguez-Mañas, L., Laosa, O., Vellas, B., Paolisso, G., Topinkova, E., Oliva-Moreno, J., Bourdel-Marchasson, I., Izquierdo, M., Hood, K., Zeyfang, A., Gambassi, G., Petrovic, M., Hardman, T. C., Kelson, M. J., Bautmans, I., Abellan, G., Barbieri, M., Peña-Longobardo, L. M., Regueme, S. C., Calvani, R., De Buyser, S., Sinclair, A. J., and on behalf of the European MID-Frail Consortium ( 2019) Effectiveness of a multimodal intervention in functionally impaired older people with type 2 diabetes mellitus. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12432.

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     Article first published online:  23 April 2019

Tobias Wollersheim, Julius J. Grunow, Niklas M. Carbon, Kurt Haas, Johannes Malleike, Sara F. Ramme, Joanna Schneider, Claudia D. Spies, Sven Märdian, Knut Mai, Simone Spuler, Jens Fielitz, Steffen Weber-Carstens

Muscle wasting and function after muscle activation and early protocol-based physiotherapy: an explorative trial
Background
Early mobilization improves physical independency of critically ill patients at hospital discharge in a general intensive care unit (ICU)-cohort. We aimed to investigate clinical and molecular benefits or detriments of early mobilization and muscle activating measures in a high-risk ICU-acquired weakness cohort.
Methods
Fifty patients with a SOFA score =9 within 72 h after ICU admission were randomized to muscle activating measures such as neuromuscular electrical stimulation or whole-body vibration in addition to early protocol-based physiotherapy (intervention) or early protocol-based physiotherapy alone (control). Muscle strength and function were assessed by Medical Research Council (MRC) score, handgrip strength and Functional Independence Measure at first awakening, ICU discharge, and 12 month follow-up. Patients underwent open surgical muscle biopsy on day 15. We investigated the impact of muscle activating measures in addition to early protocol-based physiotherapy on muscle strength and function as well as on muscle wasting, morphology, and homeostasis in patients with sepsis and ICU-acquired weakness. We compared the data with patients treated with common physiotherapeutic practice (CPP) earlier.
Results
ICU-acquired weakness occurs within the entire cohort, and muscle activating measures did not improve muscle strength or function at first awakening (MRC median [IQR]: CPP 3.3 [3.0–4.3]; control 3.0 [2.7–3.4]; intervention 3.0 [2.1–3.8]; P > 0.05 for all), ICU discharge (MRC median [IQR]: CPP 3.8 [3.4–4.4]; control 3.9 [3.3–4.0]; intervention 3.6 [2.8–4.0]; P > 0.05 for all), and 12 month follow-up (MRC median [IQR]: control 5.0 [4.3–5.0]; intervention 4.8 [4.3–5.0]; P = 0.342 for all). No signs of necrosis or inflammatory infiltration were present in the histological analysis. Myocyte cross-sectional area in the intervention group was significantly larger in comparison with the control group (type I +10%; type IIa +13%; type IIb +3%; P < 0.001 for all) and CPP (type I +36%; type IIa +49%; type IIb +65%; P < 0.001 for all). This increase was accompanied by an up-regulated gene expression for myosin heavy chains (fold change median [IQR]: MYH1 2.3 [1.1–2.7]; MYH2 0.7 [0.2–1.8]; MYH4 5.1 [2.2–15.3]) and an unaffected gene expression for TRIM63, TRIM62, and FBXO32.
Conclusions
In our patients with sepsis syndrome at high risk for ICU-acquired weakness muscle activating measures in addition to early protocol-based physiotherapy did not improve muscle strength or function at first awakening, ICU discharge, or 12 month follow-up. Yet it prevented muscle atrophy.

Wollersheim, T., Grunow, J. J., Carbon, N. M., Haas, K., Malleike, J., Ramme, S. F., Schneider, J., Spies, C. D., Märdian, S., Mai, K., Spuler, S., Fielitz, J., and Weber-Carstens, S. ( 2019) Muscle wasting and function after muscle activation and early protocol-based physiotherapy: an explorative trial. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12428.

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     Article first published online:  16 April 2019

Suey S.Y. Yeung, Esmee M. Reijnierse, Vivien K. Pham, Marijke C. Trappenburg, Wen Kwang Lim, Carel G.M. Meskers, Andrea B. Maier

Sarcopenia and its association with falls and fractures in older adults: A systematic review and meta-analysis
Sarcopenia is a potentially modifiable risk factor for falls and fractures in older adults, but the strength of the association between sarcopenia, falls, and fractures is unclear. This study aims to systematically assess the literature and perform a meta-analysis of the association between sarcopenia with falls and fractures among older adults. A literature search was performed using MEDLINE, EMBASE, Cochrane, and CINAHL from inception to May 2018. Inclusion criteria were the following: published in English, mean/median age = 65 years, sarcopenia diagnosis (based on definitions used by the original studies' authors), falls and/or fractures outcomes, and any study population. Pooled analyses were conducted of the associations of sarcopenia with falls and fractures, expressed in odds ratios (OR) and 95% confidence intervals (CIs). Subgroup analyses were performed by study design, population, sex, sarcopenia definition, continent, and study quality. Heterogeneity was assessed using the I2 statistics. The search identified 2771 studies. Thirty-six studies (52 838 individuals, 48.8% females, and mean age of the study populations ranging from 65.0 to 86.7 years) were included in the systematic review. Four studies reported on both falls and fractures. Ten out of 22 studies reported a significantly higher risk of falls in sarcopenic compared with non-sarcopenic individuals; 11 out of 19 studies showed a significant positive association with fractures. Thirty-three studies (45 926 individuals) were included in the meta-analysis. Sarcopenic individuals had a significant higher risk of falls (cross-sectional studies: OR 1.60; 95% CI 1.37–1.86, P < 0.001, I2 = 34%; prospective studies: OR 1.89; 95% CI 1.33–2.68, P < 0.001, I2 = 37%) and fractures (cross-sectional studies: OR 1.84; 95% CI 1.30–2.62, P = 0.001, I2 = 91%; prospective studies: OR 1.71; 95% CI 1.44–2.03, P = 0.011, I2 = 0%) compared with non-sarcopenic individuals. This was independent of study design, population, sex, sarcopenia definition, continent, and study quality. The positive association between sarcopenia with falls and fractures in older adults strengthens the need to invest in sarcopenia prevention and interventions to evaluate its effect on falls and fractures.

Yeung, S. S. Y., Reijnierse, E. M., Pham, V. K., Trappenburg, M. C., Lim, W. K., Meskers, C. G. M., and Maier, A. B. ( 2019) Sarcopenia and its association with falls and fractures in older adults: A systematic review and meta-analysis. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12411.

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     Article first published online:  12 April 2019

Laetitia Koppe, Denis Fouque, Kam Kalantar-Zadeh

Kidney cachexia or protein-energy wasting in chronic kidney disease: facts and numbers
Weight loss and homeostatic disturbances of both energy and protein balances are characteristics of several illnesses including cancer, heart failure, and chronic kidney disease (CKD). Different definitions have been used to describe this deleterious process. The term protein-energy wasting (PEW) has been proposed for CKD patients by the International Society of Renal Nutrition and Metabolism. Since its inception, the term PEW has been exceptionally successful, highlighted by 327 original publications referenced in PubMed over 10 years. Using this classification, several studies have confirmed that PEW is among the strongest predictors of mortality in CKD patients [hazard ratio of 3.03; confidence interval of 1.69–5.26 in 1068 haemodialysis patients and 1.40 (1.04–1.89) in 1487 non-dialysed patients across PEW stages 0 to 4]. Based on this classification, prevalence of PEW is 28% to 54% among 16 434 adults undergoing maintenance dialysis. PEW prevalence increases when renal function declines, that is, from <2% in CKD stages 1–2 to 11–54% in CKD stages 3–5. A more general definition of cachexia for all chronic diseases proposed by the Society on Sarcopenia, Cachexia and Wasting Disorders was also published concurrently. In the CKD area, we found 180 publications using ‘cachexia’ underlining that some confusion or overlap may exist. The definitions of PEW and cachexia are somewhat similar, and the main difference is that a loss of body weight >5% is a mandatory criterion for cachexia but only supportive for PEW. The recent understanding of cachexia physiopathology during CKD progression suggests that PEW and cachexia are closely related and that PEW corresponds to the initial state of a continuous process that leads to cachexia, implicating the same metabolic pathways as in other chronic diseases. Despite the success of the definition of PEW, using a more uniform term such as ‘kidney disease cachexia’ could be more helpful to design future research through collaborative groups of researchers with focus on cachexia.

Koppe, L., Fouque, D., and Kalantar-Zadeh, K. ( 2019) Kidney cachexia or protein-energy wasting in chronic kidney disease: facts and numbers. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12421.

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     Article first published online:  12 April 2019

Aditi Narsale, Rosa Moya, Jasmin Ma, Lindsey J. Anderson, Daniel Wu, Jose M. Garcia, Joanna D. Davies

Cancer-driven changes link T cell frequency to muscle strength in people with cancer: a pilot study
Background
Tumour growth can promote the loss of muscle mass and function. This is particularly disturbing because overall survival is significantly reduced in people with weaker and smaller skeletal muscle. The risk of cancer is also greater in people who are immune deficient. Muscle wasting in mice with cancer can be inhibited by infusion of CD4+ precursor T cells that restore balanced ratios of naïve, memory, and regulatory T cells. These data are consistent with the hypothesis that stronger anti-cancer T cell immunity leads to improved muscle mass and function. As a first step to testing this hypothesis, we determined whether levels of circulating T cell subsets correlate with levels of muscle strength in people with cancer.
Methods
The frequency of circulating CD4+ and CD8+ naïve, memory, and regulatory T cell subsets was quantified in 11 men with gastrointestinal cancer (aged 59.3 ± 10.1 years) and nine men without cancer (aged 60 ± 13 years), using flow cytometry. T cell marker expression was determined using real-time PCR and western blot analyses in whole blood and peripheral blood mononuclear cells. Handgrip strength, one-repetition maximum chest press, and knee extension tests were used to determine muscle strength. Performance was determined using a stair climb test. Body composition was determined using dual-energy X-ray absorptiometry scan. The Karnofsky and ECOG scales were used to assess functional impairment. Correlations between frequencies of cell subsets with strength, performance, and body composition were determined using regression analyses.
Results
Our data show significant correlations between (i) higher frequencies of CD8+ naïve (P = 0.02) and effector memory (P = 0.003) T cells and lower frequencies of CD8+ central memory T cells (P = 0.002) with stronger handgrip strength, (ii) lower frequency of regulatory cells with greater lean mass index (P = 0.04), (iii) lower frequency of CD8+ T cells that express CD95 with greater stair climb power (P = 0.003), (iv) higher frequency of T cells that co-express CD197 and CD45RA and greater one-repetition maximum knee extension strength (P = 0.008), and (iv) higher expression of CD4 in whole blood with greater functional impairment (P = 0.004) in people with cancer.
Conclusions
We have identified significant correlations between levels of T cell populations and muscle strength, performance, and body composition in people with cancer. These data justify a follow-up study with a larger cohort to test the validity of the findings.

Narsale, A., Moya, R., Ma, J., Anderson, L. J., Wu, D., Garcia, J. M., and Davies, J. D. ( 2019) Cancer-driven changes link T cell frequency to muscle strength in people with cancer: a pilot study. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12424.

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     Article first published online:  10 April 2019

Chun‐wei Li, Kang Yu, Ng Shyh‐Chang, Guo‐xun Li, Ling‐juan Jiang, Song‐lin Yu, Long‐yu Xu, Rong‐ji Liu, Zi‐jian Guo, Hai‐yan Xie, Rong‐rong Li, Jie Ying, Kang Li, Dong‐jing Li

Circulating factors associated with sarcopenia during ageing and after intensive lifestyle intervention
Background
Ageing, chronic diseases, prolonged inactivity, and inadequate nutrition pose a severe threat to skeletal muscle health and function. To date, experimental evidence suggests that ageing‐related subclinical inflammation could be an important causative factor in sarcopenia. Although inflammatory signalling has been implicated in the pathogenesis of experimental animal models of sarcopenia, few studies have surveyed the clinical association between circulating factors and muscle mass in patients before and after lifestyle interventions. In this study, we evaluated whether proinflammatory cytokines are associated with the onset of sarcopenia, which circulating factors are associated with the severity of sarcopenia, and how these factors change after lifestyle interventions in sarcopenic elderly persons.
Methods
A total of 56 elderly subjects (age ≥ 60 years) with sarcopenia and 56 elderly non‐sarcopenic subjects, who met entry criteria and had given informed consent, were selected from the Peking Union Medical College Hospital multicentre prospective longitudinal sarcopenia study for testing relevant circulating factors. Thirty‐two elderly subjects from the sarcopenic cohort completed a 12 week intensive lifestyle intervention programme with whey supplements (30 g/day) and a personalized resistance training regimen. The levels of proinflammatory cytokines and metabolic hormones, pre‐intensive and post‐intensive lifestyle interventions, were measured.
Results
The sarcopenic group was significantly older (72.05 ± 6.54 years; P < 0.001), more likely to be inactive and female (57.1% of all sarcopenic patients), and had a higher prevalence of type 2 diabetes (16% higher risk). Compared with non‐sarcopenic subjects, serum interleukin (IL)‐6, IL‐18, tumour necrosis factor‐α (TNF‐α), TNF‐like weak inducer of apoptosis (TWEAK), and leptin were significantly higher, while insulin growth factor 1, insulin, and adiponectin were significantly lower in sarcopenic patients (all P < 0.05). Logistic regression analyses revealed that high levels of TNF‐α (>11.15 pg/mL) and TWEAK (>1276.48 pg/mL) were associated with a 7.6‐fold and 14.3‐fold increased risk of sarcopenia, respectively. After adjustment for confounding variables, high levels of TWEAK were still associated with a 13.4‐fold increased risk of sarcopenia. Intensive lifestyle interventions led to significant improvements in sarcopenic patients' muscle mass and serum profiles of TWEAK, TNF‐α, IL‐18, insulin, and adiponectin (all P < 0.05).
Conclusions
High levels of the inflammatory cytokines TWEAK and TNF‐α are associated with an increased risk of sarcopenia, while the metabolic hormones insulin growth factor 1, insulin, and adiponectin are associated with a decreased risk of sarcopenia in our Chinese patient cohort. Intensive lifestyle interventions could significantly improve muscle mass, reduce inflammation, and restore metabolic hormone levels in sarcopenic patients. This trial was registered at clinicaltrials.gov as NCT02873676.

Li, C., Yu, K., Shyh‐Chang, N., Li, G., Jiang, L., Yu, S., Xu, L., Liu, R., Guo, Z., Xie, H., Li, R., Ying, J., Li, K., and Li, D. ( 2019) Circulating factors associated with sarcopenia during ageing and after intensive lifestyle intervention. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12417.

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     Article first published online:  10 April 2019

Ashley J. Smuder, Aaron B. Morton, Stephanie E. Hall, Michael P. Wiggs, Bumsoo Ahn, Nicholas R. Wawrzyniak, Kurt J. Sollanek, Kisuk Min, Oh Sung Kwon, W. Bradley Nelson, Scott K. Powers

Effects of exercise preconditioning and HSP72 on diaphragm muscle function during mechanical ventilation
Background
Mechanical ventilation (MV) is a life‐saving measure for patients in respiratory failure. However, prolonged MV results in significant diaphragm atrophy and contractile dysfunction, a condition referred to as ventilator‐induced diaphragm dysfunction (VIDD). While there are currently no clinically approved countermeasures to prevent VIDD, increased expression of heat shock protein 72 (HSP72) has been demonstrated to attenuate inactivity‐induced muscle wasting. HSP72 elicits cytoprotection via inhibition of NF‐κB and FoxO transcriptional activity, which contribute to VIDD. In addition, exercise‐induced prevention of VIDD is characterized by an increase in the concentration of HSP72 in the diaphragm. Therefore, we tested the hypothesis that increased HSP72 expression is required for the exercise‐induced prevention of VIDD. We also determined whether increasing the abundance of HSP72 in the diaphragm, independent of exercise, is sufficient to prevent VIDD.
Methods
Cause and effect was determined by inhibiting the endurance exercise‐induced increase in HSP72 in the diaphragm of exercise trained animals exposed to prolonged MV via administration of an antisense oligonucleotide targeting HSP72. Additional experiments were performed to determine if increasing HSP72 in the diaphragm via genetic (rAAV‐HSP72) or pharmacological (BGP‐15) overexpression is sufficient to prevent VIDD.
Results
Our results demonstrate that the exercise‐induced increase in HSP72 protein abundance is required for the protective effects of exercise against VIDD. Moreover, both rAAV‐HSP72 and BGP‐15‐induced overexpression of HSP72 were sufficient to prevent VIDD. In addition, modification of HSP72 in the diaphragm is inversely related to the expression of NF‐κB and FoxO target genes.
Conclusions
HSP72 overexpression in the diaphragm is an effective intervention to prevent MV‐induced oxidative stress and the transcriptional activity of NF‐κB and FoxO. Therefore, overexpression of HSP72 in the diaphragm is a potential therapeutic target to protect against VIDD.

Smuder, A. J., Morton, A. B., Hall, S. E., Wiggs, M. P., Ahn, B., Wawrzyniak, N. R., Sollanek, K. J., Min, K., Kwon, O. S., Nelson, W. B., and Powers, S. K. ( 2019) Effects of exercise preconditioning and HSP72 on diaphragm muscle function during mechanical ventilation. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12427.

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     Article first published online:  05 April 2019

Maurizio Muscaritoli, Alessio Molfino, Ferdinando Scala, Kalliopi Christoforidi, Isabelle Manneh‐Vangramberen, Francesco De Lorenzo

Nutritional and metabolic derangements in Mediterranean cancer patients and survivors: the ECPC 2016 survey
Background
The prevalence of nutritional derangements in patients with cancer is high. This survey assessed patients' awareness of cancer‐related nutritional issues and evaluated how important they perceive the impact of nutrition on cancer and treatment to be.
Methods
A structured questionnaire was developed to determine: presence of feeding problems, perception of nutrition importance, and perception of physicians' approach to nutrition. The European Cancer Patient Coalition disseminated the questionnaire to its members in 10 countries. The Mediterranean cluster (Italy, Spain, and Greece) was analysed separately to further determine specific patterns in answers.
Results
In total, 907 respondents completed the questionnaire (68.8% female participants; 51.7% with cancer; 48.3% cancer survivors; 59.3% diagnosed with cancer ≤3 years ago; 46.2% receiving treatment for <1 year). Feeding problems during illness/therapy were experienced by 72.5% (628/867) of all respondents (Italian: 90.0%, 117/130), although up to 53.9% (467/867) reported that physicians did not check their feeding status. Overall, 69.6% (586/842) of respondents reported weight loss after cancer diagnosis (moderate to severe: 36.7%, 309/842). For Italian respondents, the percentages of overall weight loss and moderate‐to‐severe weight loss were 85.1% (109/128) and 70.3% (90/128), respectively. Only 35.0% (295/842) of all respondents reported having their weight measured regularly during treatment; 45.7% (385/842) believed their physician considered cancer‐related weight loss unimportant. Respondents [all: 56.9% (472/830); Italian: 73.0% (92/126); Spanish: 68.9% (42/61); Greek: 79.7% (47/59)] were unaware of supplements' negative effects during therapy or the need to inform their physician about these supplements [all: 43.6% (362/830); Italian: 55.6% (70/126); Spanish: 47.5% (29/61); Greek: 49.2% (29/59)]. The term ‘cachexia’ was generally unknown to respondents [all: 72.9% (603/827); Italian: 64.3% (81/126); Spanish: 68.9% (42/61); Greek: 47.5% (28/59)] and most respondents [all: 92.4% (764/827); Italian: 91.3% (115/126); Spanish: 91.8% (56/61); Greek: 86.4% (51/59)] received no cachexia‐related information.
Conclusions
Patients reported differences in perspective between them and physicians on cancer‐related nutritional issues and the specific nutritional approaches available for cancer treatment. Increasing physician focus on nutrition during treatment, particularly among Italian physicians, and providing information on optimizing nutrition to patients are essential factors to improving patients' quality of life.

Muscaritoli, M., Molfino, A., Scala, F., Christoforidi, K., Manneh‐Vangramberen, I., and De Lorenzo, F. ( 2019) Nutritional and metabolic derangements in Mediterranean cancer patients and survivors: the ECPC 2016 survey. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12420.

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     Article first published online:  02 April 2019

Simone Perna, Daniele Spadaccini, Mariangela Rondanelli

Sarcopenic obesity: time to target the phenotypes
no abstract

Perna, S., Spadaccini, D., and Rondanelli, M. ( 2019) Sarcopenic obesity: time to target the phenotypes. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12425.

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     Article first published online:  02 April 2019

Yen‐Chung Lin, Yi‐Jen Lai, Yi‐Chun Lin, Chiung‐Chi Peng, Kuan‐Chou Chen, Ming‐Tsang Chuang, Mai‐Szu Wu, Tzu‐Hao Chang

Effect of weight loss on the estimated glomerular filtration rates of obese patients at risk of chronic kidney disease: the RIGOR‐TMU study
Background
Weight‐reduction therapies, including bariatric surgery (BS), are standard treatments for severely obese patients with type 2 diabetes; however, the outcomes of these therapies are inconclusive for obese patients with chronic kidney disease (CKD). This study aimed to investigate the effects of BS or non‐surgical interventions on the estimated glomerular filtration rate (eGFR) and to determine whether BS can be recommended for renal function preservation based on body mass index (BMI) and eGFR changes in obese patients with CKD.
Methods
This study used data from the weight Reduction Intervention on GFR in Obese Patients with Renal Impairment‐Taipei Medical University (TMU) study, which was a large, long‐term, propensity score‐matched cohort study based on clinical data from patients who registered at weight‐reduction centres at TMU and its affiliated hospitals from 2008 to 2016. The patients were stratified according to whether they had undergone BS and into the mild, moderate, and high CKD risk groups using the Kidney Disease: Improving Global Outcomes guidelines. The primary outcome was the eGFR calculated using the Taiwan Chronic Kidney Disease‐Epidemiology Collaboration equation. Cox regression models were used to determine hazard ratios (HRs) for eGFR decreases ≥25%.
Results
A total of 4332 obese patients were enrolled in this study. After propensity score matching, 1620 patients, including 60.2% women, with a mean age of 36.5 (9.9) years were divided into BS or non‐surgery groups (n = 810 per group). The overall mean eGFRs increased by 4.4 (14) mL/min·1.73 m2 and decreased by 6.4 (16.0) mL/min·1.73 m2 in the BS and non‐surgery groups, respectively. The decrease in BMI in the BS and non‐surgery groups were 2.5 and 1.3 kg/m2, respectively. In the moderate/high CKD risk BS group, a significant correlation was evident between an increased eGFR and a reduced BMI (Spearman's correlation −0.229, P < 0.001). The Cox regression analysis showed that the BS group had a significantly lower risk of an eGFR decline ≥25% at 12 months [adjusted HR (aHR) 0.47, P = 0.03). After BS, obese patients with hypertension or albuminuria had significantly lower risks of eGFR declines ≥25% (aHR 0.37, P = 0.02 and aHR 0.13, P = 0.0018, respectively).
Conclusions
Bariatric surgery was associated with eGFR preservation in all obese patients and, particularly, in those with moderate‐to‐high CKD risks. A longer term outcome study is warranted to determine the benefits of BS for CKD patients.

Lin, Y.‐C., Lai, Y.‐J., Lin, Y.‐C., Peng, C.‐C., Chen, K.‐C., Chuang, M.‐T., Wu, M.‐S., and Chang, T.‐H. ( 2019) Effect of weight loss on the estimated glomerular filtration rates of obese patients at risk of chronic kidney disease: the RIGOR‐TMU study. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12423.

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     Article first published online:  02 April 2019

Meghan C. Hughes, Sofhia V. Ramos, Patrick C. Turnbull, Irena A. Rebalka, Andrew Cao, Cynthia M.F. Monaco, Nina E. Varah, Brittany A. Edgett, Jason S. Huber, Peyman Tadi, Luca J. Delfinis, U. Schlattner, Jeremy A. Simpson, Thomas J. Hawke, Christopher G.R. Perry

Early myopathy in Duchenne muscular dystrophy is associated with elevated mitochondrial H2O2 emission during impaired oxidative phosphorylation
Background
Muscle wasting and weakness in Duchenne muscular dystrophy (DMD) causes severe locomotor limitations and early death due in part to respiratory muscle failure. Given that current clinical practice focuses on treating secondary complications in this genetic disease, there is a clear need to identify additional contributions in the aetiology of this myopathy for knowledge‐guided therapy development. Here, we address the unresolved question of whether the complex impairments observed in DMD are linked to elevated mitochondrial H2O2 emission in conjunction with impaired oxidative phosphorylation. This study performed a systematic evaluation of the nature and degree of mitochondrial‐derived H2O2 emission and mitochondrial oxidative dysfunction in a mouse model of DMD by designing in vitro bioenergetic assessments that attempt to mimic in vivo conditions known to be critical for the regulation of mitochondrial bioenergetics.
Methods
Mitochondrial bioenergetics were compared with functional and histopathological indices of myopathy early in DMD (4 weeks) in D2.B10‐DMDmdx/2J mice (D2.mdx)—a model that demonstrates severe muscle weakness. Adenosine diphosphate's (ADP's) central effect of attenuating H2O2 emission while stimulating respiration was compared under two models of mitochondrial‐cytoplasmic phosphate exchange (creatine independent and dependent) in muscles that stained positive for membrane damage (diaphragm, quadriceps, and white gastrocnemius).
Results
Pathway‐specific analyses revealed that Complex I‐supported maximal H2O2 emission was elevated concurrent with a reduced ability of ADP to attenuate emission during respiration in all three muscles (mH2O2: +17 to +197% in D2.mdx vs. wild type). This was associated with an impaired ability of ADP to stimulate respiration at sub‐maximal and maximal kinetics (−17 to −72% in D2.mdx vs. wild type), as well as a loss of creatine‐dependent mitochondrial phosphate shuttling in diaphragm and quadriceps. These changes largely occurred independent of mitochondrial density or abundance of respiratory chain complexes, except for quadriceps. This muscle was also the only one exhibiting decreased calcium retention capacity, which indicates increased sensitivity to calcium‐induced permeability transition pore opening. Increased H2O2 emission was accompanied by a compensatory increase in total glutathione, while oxidative stress markers were unchanged. Mitochondrial bioenergetic dysfunctions were associated with induction of mitochondrial‐linked caspase 9, necrosis, and markers of atrophy in some muscles as well as reduced hindlimb torque and reduced respiratory muscle function.
Conclusions
These results provide evidence that Complex I dysfunction and loss of central respiratory control by ADP and creatine cause elevated oxidant generation during impaired oxidative phosphorylation. These dysfunctions may contribute to early stage disease pathophysiology and support the growing notion that mitochondria are a potential therapeutic target in this disease.

Hughes, M. C., Ramos, S. V., Turnbull, P. C., Rebalka, I. A., Cao, A., Monaco, C. M. F., Varah, N. E., Edgett, B. A., Huber, J. S., Tadi, P., Delfinis, L. J., Schlattner, U., Simpson, J. A., Hawke, T. J., and Perry, C. G. R. ( 2019) Early myopathy in Duchenne muscular dystrophy is associated with elevated mitochondrial H2O2 emission during impaired oxidative phosphorylation. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12405.

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     Article first published online:  01 April 2019

Sami Antoun, Hugues Morel, Pierre‐Jean Souquet, Veerle Surmont, David Planchard, Franck Bonnetain, Pascal Foucher, Thomas Egenod, Ivan Krakowski, Hélène Gaudin, Didier Debieuvre

Staging of nutrition disorders in non‐small‐cell lung cancer patients: utility of skeletal muscle mass assessment

Background
An international consensus proposed in 2011 a definition and classification system for cachexia (CAX), mainly based on weight loss, sarcopenia [skeletal muscle mass (SMM) loss], inflammation, and anorexia. The aim of this study was to stage CAX in non‐small‐cell lung cancer (NSCLC) patients by using a classification based on the Fearon criteria and supported by quantifiable parameters.
Methods
This was a cross‐sectional and non‐interventional multicentre study. SMM was assessed by analysing L3 computed tomography‐scan images. Patients completed the anorexia/CAX subscale of the Functional Assessment of Anorexia/Cachexia Therapy, EORTC QLQ‐C30 quality of life (QoL) and International Physical Activity Questionnaire (IPAQ).
Results
Patients were recruited in 56 sites. The analysis population comprised 531 patients, and SMM was assessed in 312 patients. Male patients were 66.5%, with a mean (SD) age of 65.2 (10.0) years, 79.9% were PS 0–1, and the tumour stage was mainly IIIB‐IV (87.3%). Overall, 38.7% of patients had CAX, 33.8% pre‐CAX, and 0.9% refractory CAX. Molecular tumour profiles were significantly associated with the presence of CAX: 23.9% in EGFR, ALK, ROS1, BRAF, or HER2+ patients, 41.4% in K‐RAS+, and 43.2% in patients with no molecular abnormality (P = 0.003). The more advanced the CAX stage, the poorer the scores of functional items of the QoL (P < 0.001) and International Physical Activity Questionnaire (P < 0.001). Sarcopenia was present in 66.7% of CAX and 68.5% of pre‐CAX patients. Overall, 43.8% of pre‐CAX patients had only sarcopenia with limited weight loss (≤2%) and no anorexia.
Conclusions
This is the first study to show the distribution of CAX in a population of NSCLC patients and an association between molecular abnormality in NSCLC and CAX. The original Fearon classification for CAX stages was supported by the associated functional QoL scores and physical activity levels, resulting in a clinically relevant system for detection of early stages of CAX.

Antoun, S., Morel, H., Souquet, P.‐J., Surmont, V., Planchard, D., Bonnetain, F., Foucher, P., Egenod, T., Krakowski, I., Gaudin, H., and Debieuvre, D. ( 2019) Staging of nutrition disorders in non‐small‐cell lung cancer patients: utility of skeletal muscle mass assessment. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12418.

ABSTRACT | PDF |

 

     Article first published online:  01 April 2019

Dawit A. Gonçalves, Wilian A. Silveira, Leandro H. Manfredi, Flávia A. Graça, Andrea Armani, Enrico Bertaggia, Brian T. O´Neill, Natalia Lautherbach, Juliano Machado, Leonardo Nogara, Marcelo G. Pereira, Diletta Arcidiacono, Stefano Realdon, C. Ronald Kahn, Marco Sandri, Isis C. Kettelhut, Luiz Carlos C. Navegantes

Insulin/IGF1 signalling mediates the effects of β2‐adrenergic agonist on muscle proteostasis and growth

Background
Stimulation of β2‐adrenoceptors can promote muscle hypertrophy and fibre type shift, and it can counteract atrophy and weakness. The underlying mechanisms remain elusive.
Methods
Fed wild type (WT), 2‐day fasted WT, muscle‐specific insulin (INS) receptor (IR) knockout (M‐IR−/−), and MKR mice were studied with regard to acute effects of the β2‐agonist formoterol (FOR) on protein metabolism and signalling events. MKR mice express a dominant negative IGF1 receptor, which blocks both INS/IGF1 signalling. All received one injection of FOR (300 μg kg−1 subcutaneously) or saline. Skeletal muscles and serum samples were analysed from 30 to 240 min. For the study of chronic effects of FOR on muscle plasticity and function as well as intracellular signalling pathways, fed WT and MKR mice were treated with formoterol (300 μg kg−1 day−1) for 30 days.
Results
In fed and fasted mice, one injection of FOR inhibited autophagosome formation (LC3‐II content, 65%, P ≤ 0.05) that was paralleled by an increase in serum INS levels (4‐fold to 25‐fold, P ≤ 0.05) and the phosphorylation of Akt (4.4‐fold to 6.5‐fold, P ≤ 0.05) and ERK1/2 (50% to two‐fold, P ≤ 0.05). This led to the suppression (40–70%, P ≤ 0.05) of the master regulators of atrophy, FoxOs, and the mRNA levels of their target genes. FOR enhanced (41%, P ≤ 0.05) protein synthesis only in fed condition and stimulated (4.4‐fold to 35‐fold, P ≤ 0.05) the prosynthetic Akt/mTOR/p70S6K pathway in both fed and fasted states. FOR effects on Akt signalling during fasting were blunted in both M‐IR−/− and MKR mice. Inhibition of proteolysis markers by FOR was prevented only in MKR mice. Blockade of PI3K/Akt axis and mTORC1, but not ERK1/2, in fasted mice also suppressed the acute FOR effects on proteolysis and autophagy. Chronic stimulation of β2‐adrenoceptors in fed WT mice increased body (11%, P ≤ 0.05) and muscle (15%, P ≤ 0.05) growth and downregulated atrophy‐related genes (30–40%, P ≤ 0.05), but these effects were abolished in MKR mice. Increases in muscle force caused by FOR (WT, 24%, P ≤ 0.05) were only partially impaired in MKR mice (12%, P ≤ 0.05), and FOR‐induced slow‐to‐fast fibre type shift was not blocked at all in these animals. In MKR mice, FOR also restored the lower levels of muscle SDH activity to basal WT values and caused a marked reduction (57%, P ≤ 0.05) in the number of centrally nucleated fibers.
Conclusions
NS/IGF1 signalling is necessary for the anti‐proteolytic and hypertrophic effects of in vivo β2‐adrenergic stimulation and appears to mediate FOR‐induced enhancement of protein synthesis. INS/IGF1 signalling only partially contributes to gain in strength and does not mediate fibre type transition induced by FOR.

Gonçalves, D. A., Silveira, W. A., Manfredi, L. H., Graça, F. A., Armani, A., Bertaggia, E., O´Neill, B. T., Lautherbach, N., Machado, J., Nogara, L., Pereira, M. G., Arcidiacono, D., Realdon, S., Kahn, C. R., Sandri, M., Kettelhut, I. C., and Navegantes, L. C. C. ( 2019) Insulin/IGF1 signalling mediates the effects of β2‐adrenergic agonist on muscle proteostasis and growth. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12395.

ABSTRACT | PDF |

 

     Article first published online:  28 March 2019 

Ilanna Marques Gomes da Rocha, Aline Marcadenti, Galtieri Otávio Cunha de Medeiros, Ricardo Andrade Bezerra,
Juliana Florinda de Mendonça Rego, Maria Cristina Gonzalez, Ana Paula Trussardi Fayh

Is cachexia associated with chemotherapy toxicities in gastrointestinal cancer patients? A prospective study

Background
Chemotherapy is an effective treatment with good clinical response in patients with cancer. However, it can cause exacerbated toxicities in patients and consequently change the course of treatment. Some factors may interfere with this toxicity such as body composition, especially in gastrointestinal cancer. The aim of this study was to evaluate the effects of body composition, nutritional status, and functional capacity scale in predicting the occurrence of toxicities in gastrointestinal cancer patients during chemotherapy treatment.
Methods
This is a prospective study with gastrointestinal cancer patients at the beginning of chemotherapy treatment. Sarcopenia and muscle attenuation were assessed using the skeletal muscle index from computerized tomography by measuring cross‐sectional areas of the L3 tissue (cm2/m2). Cachexia was graded according to involuntary weight loss associated with sarcopenia. Nutritional status was assessed by using anthropometric evaluation and Patient‐Generated Subjective Global Assessment. Functional capacity was evaluated by handgrip strength and Eastern Cooperative Oncology Group (ECOG) Performance Status scale. Haematological gastrointestinal and dose‐limiting toxicities (DLTs) were defined according to National Cancer Institute Common Toxicity Criteria. The associations among sarcopenia, cachexia, nutritional status, and functional capacity with DLT were assessed by univariate and multivariate Cox regression model.
Results
A total of 60 patients were evaluated (55% male, 60.9 ± 14.0 years) and followed up for a mean of 55 days. Most patients had normal weight (44.2%) and good ECOG Performance Status (≤1) at baseline (78%). During the chemotherapy period, the most prevalent toxicities were diarrhoea, nausea, and anorexia, but the presence of DLT was similar between cycles (P > 0.05). Cachexia was associated with a higher toxicity manifested by diarrhoea (P = 0.02), nausea (P = 0.02), and anorexia (P < 0.01 and P = 0.03 at Cycles 1 and 2, respectively). Sarcopenic and cachetic individuals experienced more toxicities and DLT during chemotherapy. The only factors associated with DLT in the multivariate Cox regression analyses including the presence of metastasis and the chemotherapy protocol were cachexia and the ECOG scale (P < 0.001 for both).
Conclusions
Cachexia and ECOG score may identify patients with an increased risk for developing severe toxicity events during chemotherapy treatment for gastrointestinal cancer.

Rocha, I. M. G., Marcadenti, A., Medeiros, G. O. C., Bezerra, R. A., Rego, J. F. M., Gonzalez, M. C., and Fayh, A. P. T. ( 2019) Is cachexia associated with chemotherapy toxicities in gastrointestinal cancer patients? A prospective study. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12391.

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     Article first published online:  27 March 2019 

Khalid Alyodawi, Wilbert P. Vermeij, Saleh Omairi, Oliver Kretz, Mark Hopkinson, Francesca Solagna, Barbara Joch, Renata M.C. Brandt, Sander Barnhoorn, Nicole van Vliet, Yanto Ridwan, Jeroen Essers, Robert Mitchell, Taryn Morash, Arja Pasternack, Olli Ritvos, Antonios Matsakas, Henry Collins‐Hooper, Tobias B. Huber, Jan H.J. Hoeijmakers, Ketan Patel

Compression of morbidity in a progeroid mouse model through the attenuation of myostatin/activin signalling

Background
One of the principles underpinning our understanding of ageing is that DNA damage induces a stress response that shifts cellular resources from growth towards maintenance. A contrasting and seemingly irreconcilable view is that prompting growth of, for example, skeletal muscle confers systemic benefit.
Methods
To investigate the robustness of these axioms, we induced muscle growth in a murine progeroid model through the use of activin receptor IIB ligand trap that dampens myostatin/activin signalling. Progeric mice were then investigated for neurological and muscle function as well as cellular profiling of the muscle, kidney, liver, and bone.
Results
We show that muscle of Ercc1Δ/− progeroid mice undergoes severe wasting (decreases in hind limb muscle mass of 40–60% compared with normal mass), which is largely protected by attenuating myostatin/activin signalling using soluble activin receptor type IIB (sActRIIB) (increase of 30–62% compared with untreated progeric). sActRIIB‐treated progeroid mice maintained muscle activity (distance travel per hour: 5.6 m in untreated mice vs. 13.7 m in treated) and increased specific force (19.3 mN/mg in untreated vs. 24.0 mN/mg in treated). sActRIIb treatment of progeroid mice also improved satellite cell function especially their ability to proliferate on their native substrate (2.5 cells per fibre in untreated progeroids vs. 5.4 in sActRIIB‐treated progeroids after 72 h in culture). Besides direct protective effects on muscle, we show systemic improvements to other organs including the structure and function of the kidneys; there was a major decrease in the protein content in urine (albumin/creatinine of 4.9 sActRIIB treated vs. 15.7 in untreated), which is likely to be a result in the normalization of podocyte foot processes, which constitute the filtration apparatus (glomerular basement membrane thickness reduced from 224 to 177 nm following sActRIIB treatment). Treatment of the progeric mice with the activin ligand trap protected against the development of liver abnormalities including polyploidy (18.3% untreated vs. 8.1% treated) and osteoporosis (trabecular bone volume; 0.30 mm3 in treated progeroid mice vs. 0.14 mm3 in untreated mice, cortical bone volume; 0.30 mm3 in treated progeroid mice vs. 0.22 mm3 in untreated mice). The onset of neurological abnormalities was delayed (by ~5 weeks) and their severity reduced, overall sustaining health without affecting lifespan.
Conclusions
This study questions the notion that tissue growth and maintaining tissue function during ageing are incompatible mechanisms. It highlights the need for future investigations to assess the potential of therapies based on myostatin/activin blockade to compress morbidity and promote healthy ageing.

Alyodawi, K., Vermeij, W. P., Omairi, S., Kretz, O., Hopkinson, M., Solagna, F., Joch, B., Brandt, R. M. C., Barnhoorn, S., Vliet, N., Ridwan, Y., Essers, J., Mitchell, R., Morash, T., Pasternack, A., Ritvos, O., Matsakas, A., Collins‐Hooper, H., Huber, T. B., Hoeijmakers, J. H. J., and Patel, K. ( 2019) Compression of morbidity in a progeroid mouse model through the attenuation of myostatin/activin signalling. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12404.

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     Article first published online:  25 March 2019 

Maxime Moreillon, Sonia Conde Alonso, Nicholas T. Broskey, Chiara Greggio, Cyril Besson, Valentin Rousson, Francesca Amati

Hybrid fiber alterations in exercising seniors suggest contribution to fast-to-slow muscle fiber shift

Background
Human skeletal muscle is composed of a functional and metabolic continuum of slow (Type I) and fast fibers (IIa and IIx). Hybrid fibers co-expressing different myosin heavy chains are also present and seem to be more prominent in aging muscle. Their role is debated; hybrid fibers were reported either in a transitional state, between slow and fast fibers, or as fixed individual entities. This study examined the fate of hybrid fibers with an endurance exercise intervention in an elderly sedentary population.
Methods
Twenty-two sedentary healthy elderly men and women underwent a 16-week supervised endurance exercise intervention. Eighteen endurance-trained age- and gender-matched volunteers served as controls. Fiber type distribution was determined by immunohistochemistry on vastus lateralis muscle biopsies pre-intervention and post-intervention.
Results
A total of 13840 fibers were analyzed. At baseline, a Type II dominant fiber profile was observed compared with the control group, with more Type IIa (P = 0.0301) and Type IIx fibers (P = 0.0328). Hybrid fibers represented almost 5% of total muscle fibers in both groups. There was no significant difference between groups (I–IIa, P = 0.6719 and IIa–IIx, P = 0.0998). Intervention triggered qualitative dynamics towards an increase in Type I, and decrease in Type II fibers, paralleled by an increase in I–IIa hybrids (P = 0.0301).
Conclusions
The present study is, to our knowledge, the first to examine hybrid muscle fiber type adaptations to an endurance exercise intervention in the elderly. Hybrid fiber proportions did not differ between chronic sedentary state and chronic endurance-trained state. Exercise intervention increased Type I–IIa hybrid fibers along with shift dynamics in other fiber types suggesting the contribution of hybrid fiber to a fast-to-slow fiber type transition, eventually serving as intermediate reservoir from one monomorphic myosin heavy chain expressing fiber type to another. This finding favours the transitional theory regarding hybrid muscle fibers and exercise, crucial to understanding reversible mechanisms of sarcopenia and development of prevention measures.

Moreillon, M., Conde Alonso, S., Broskey, N. T., Greggio, C., Besson, C., Rousson, V., and Amati, F. ( 2019) Hybrid fiber alterations in exercising seniors suggest contribution to fast-to-slow muscle fiber shift. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12410.

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     Article first published online:  25 March 2019 

Suzanne P. Stam, Michele F. Eisenga, Antonio W. Gomes-Neto, Marco van Londen, Vincent E. de Meijer, André P. van Beek, Ron T. Gansevoort, Stephan J.L. Bakker

Muscle mass determined from urinary creatinine excretion rate, and muscle performance in renal transplant recipients

Background
Muscle mass, as determined from 24-h urinary creatinine excretion rate (CER), is an independent predictor for mortality and graft failure in renal transplant recipients (RTR). It is currently unknown whether CER is comparable with healthy controls after transplantation and whether it reflects muscle performance besides muscle mass. We aimed to compare urinary CER and muscle performance between RTR and healthy controls and to investigate whether urinary CER is associated with muscle performance in RTR.
Methods
We included RTR, transplanted between 1975 and 2016 in the University Medical Center Groningen. Healthy controls were subjects screened for kidney donation. CER was calculated from a 24-h urine collection. Muscle performance was assessed by handgrip strength, sit-to-stand test, and 2-min walk test. Statistical analyses were performed using linear regression analyses.
Results
We included 184 RTR (mean age 56.9 ± 11.9 years, 54% male recipient) and 78 healthy controls (age 57.9 ± 9.9, 47% male recipient). RTR were at a median time of 4.0 (1.1–8.8) years after transplantation. Mean CER was lower in RTR compared to healthy controls (11.7 ± 4.0 vs. 13.1 ± 5.2 mmol/24 h; P = 0.04). Significantly poorer results in muscle performance were found in RTR compared to controls for the handgrip strength (30.5 [23.7–41.1] N vs. 38.3 [29.3–46.0] N, P < 0.001) and the 2-min walk test (151.5 ± 49.2 m vs. 172.3 ± 12.2 m, P < 0.001) but not for the sit-to-stand (12.2 ± 3.3 m vs. 11.9 ± 2.8 m, P = 0.46). In RTR, CER was significantly associated with handgrip strength (std. ß 0.33; P < 0.001), independent of adjustment for potential confounders. In RTR, CER was neither associated with the time used for the sit-to-stand test (std. ß -0.09; P = 0.27) nor with the distance covered during the 2-min walk test (std. ß 0.07; P = 0.40).
Conclusions
Muscle mass as measured by CER in RTR is lower compared to controls. CER is positively associated with muscle performance in RTR. The results demonstrate that CER does not only reflect muscle mass but also muscle performance in this patient setting. Determination of CER could be an interesting addition to the imaging technique armamentarium available and applied for evaluation of muscle mass in clinical intervention studies and observational studies.

Stam, S. P., Eisenga, M. F., Gomes-Neto, A. W., Londen, M., Meijer, V. E., Beek, A. P., Gansevoort, R. T., and Bakker, S. J. L. ( 2019) Muscle mass determined from urinary creatinine excretion rate, and muscle performance in renal transplant recipients. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12399.

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     Article first published online:  25 March 2019 

Yoshinaga Okugawa, Yuji Toiyama, Keun Hur, Akira Yamamoto, Chengzeng Yin, Shozo Ide, Takahito Kitajima, Hiroyuki Fujikawa, Hiromi Yasuda, Yuhki Koike, Yoshiki Okita, Junichiro Hiro, Shigeyuki Yoshiyama, Toshimitsu Araki, Chikao Miki, Donald C. McMillan, Ajay Goel, Masato Kusunoki

Circulating miR-203 derived from metastatic tissues promotes myopenia in colorectal cancer patients

Background
Sarcopenia frequently occurs in metastatic cancer patients. Emerging evidence has revealed that various secretory products from metastatic tumours can influence host organs and promote sarcopenia in patients with malignancies. Furthermore, the biological functions of microRNAs in cell-to-cell communication by incorporating into neighbouring or distal cells, which have been gradually elucidated in various diseases, including sarcopenia, have been elucidated.
Methods
We evaluated psoas muscle mass index (PMI) and intramuscular adipose tissue content (IMAC) using pre-operative computed tomography imaging in 183 colorectal cancer (CRC) patients. miR-203 expression levels in CRC tissues and pre-operative serum were evaluated using quantitative polymerase chain reaction. Functional analysis of miR-203 overexpression was investigated in human skeletal muscle cells (SkMCs), and cells were analysed for proliferation and apoptosis. Expressions of several putative miR-203 target genes (CASP3, CASP10, BIRC5, BMI1, BIRC2, and BIRC3) in SKMCs were validated.
Results
A total of 183 patients (108 men and 75 women) were included. The median age of enrolled patients at diagnosis was 68.0 years (range 35–89 years). High IMAC status significantly correlated with female gender (P = 0.004) and older age (P = 0.0003); however, no other clinicopathological factors correlated with IMAC status in CRC patients. In contrast, decreased PMI significantly correlated with female gender (P = 0.006) and all well-established disease development factors, including advanced T stage (P = 0.035), presence of venous invasion (P = 0.034), lymphovascular invasion (P = 0.012), lymph node (P = 0.001), distant metastasis (P = 0.002), and advanced Union for International Cancer Control tumour–node–metastasis stage classification (P = 0.0004). Although both high IMAC status and low PMI status significantly correlated with poor overall survival (IMAC: P = 0.0002; PMI: P < 0.0001; log-rank test) and disease-free survival (IMAC: P = 0.0003; PMI: P = 0.0002; log-rank test), multivariate Cox's regression analysis revealed that low PMI was an independent prognostic factor for both overall survival (hazard ratio: 4.69, 95% confidence interval (CI): 2.19–10, P = 0.0001) and disease-free survival (hazard ratio: 2.33, 95% CI: 1.14–4.77, P = 0.021) in CRC patients. Serum miR-203 expression negatively correlated with pre-operative PMI level (P = 0.0001, ? = -0.25), and multivariate logistic regression analysis revealed that elevated serum miR-203 was an independent risk factor for myopenia (low PMI) in CRC patients (odds ratio: 5.16, 95% CI: 1.8–14.8, P = 0.002). Overexpression of miR-203 inhibited cell proliferation and induced apoptosis via down-regulation of BIRC5 (survivin) expression in human SkMC line.
Conclusions
Assessment of serum miR-203 expression could be used for risk assessment of myopenia, and miR-203 might be a novel therapeutic target for inhibition of myopenia in CRC.

Okugawa, Y., Toiyama, Y., Hur, K., Yamamoto, A., Yin, C., Ide, S., Kitajima, T., Fujikawa, H., Yasuda, H., Koike, Y., Okita, Y., Hiro, J., Yoshiyama, S., Araki, T., Miki, C., McMillan, D. C., Goel, A., and Kusunoki, M. ( 2019) Circulating miR-203 derived from metastatic tissues promotes myopenia in colorectal cancer patients. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12403.

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     Article first published online:  24 March 2019 

Marc Sim, Joshua R. Lewis, Lauren C. Blekkenhorst, Catherine P. Bondonno, Amanda Devine, Kun Zhu, Peter Peeling, Richard L. Prince, Jonathan M. Hodgson

Higher dietary nitrate intake is associated with better muscle function in older women

Background
In younger individuals, dietary nitrate supplementation has been shown to improve short-term vascular and muscle function. The role of higher habitual nitrate intake as part of a typical diet on muscle function in ageing has not been investigated. A cross-sectional study of relationships between dietary nitrate and measures of muscle function in older community-dwelling Australian women (n = 1420, =70 years) was undertaken.
Methods
Participants completed a semi-quantitative food frequency questionnaire assessing dietary intake over the previous year. Total nitrate from vegetables and non-vegetable sources was calculated from a validated instrument that quantified the nitrate content of food recorded within the food frequency questionnaire. Handgrip strength and timed-up-and-go (TUG) were assessed, representing muscle strength and physical function, respectively. Cut-points for weak grip strength (<22 kg) and slow TUG (>10.2 s) were selected due to their association with adverse outcomes. Linear and logistic regressions were used to examine the relationship between total nitrate intake and muscle function measures.
Results
Mean ± standard deviation (SD) total nitrate intake was 79.5 ± 31.2 mg/day, of which 84.5% came from vegetables. Across the unadjusted tertiles of nitrate intake (<64.2 mg/day; 64.2 to <89.0 mg/day; =89.0 mg/day), women in the highest tertile had a 4% stronger grip strength and a 5% faster TUG performance compared with the lowest tertile. In multivariable-adjusted models, each SD higher nitrate intake (31.2 mg/day) was associated with stronger grip strength (per kilogram, ß 0.31, P = 0.027) and faster TUG (per second, ß -0.27, P = 0.001). The proportion of women with weak grip strength (<22 kg) or slow TUG (>10.2 s) was 61.0% and 36.9%, respectively. Each SD higher nitrate intake (31.2 mg/day) was associated with lower odds for weak grip strength (OR 0.84, 95% CI 0.74–0.95, P = 0.005) and slow TUG (OR 0.86, 95% CI 0.76–0.98, P = 0.021). Compared with women in the lowest tertile of nitrate intake, women in the highest nitrate intake tertile had lower odds for weak grip strength (OR 0.65, 95% CI 0.49–0.87, Ptrend=0.004) and slow TUG (OR 0.72, 95% CI 0.53–0.97, Ptrend = 0.044).
Conclusions
This investigation highlights potential benefits of nitrate-rich diets on muscle strength and physical function in a large cohort of older women. Considering poor muscle strength and physical function is associated with a range of adverse health outcomes such as falling, fractures, cardiovascular disease, and mortality, increasing dietary nitrate, especially though vegetable consumption may be an effective way to limit age-related declines in muscle function.

Sim, M., Lewis, J. R., Blekkenhorst, L. C., Bondonno, C. P., Devine, A., Zhu, K., Peeling, P., Prince, R. L., and Hodgson, J. M. ( 2019) Higher dietary nitrate intake is associated with better muscle function in older women. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12413.

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     Article first published online:  20 March 2019 

Lynette J. Oost, Monika Kustermann, Andrea Armani, Bert Blaauw, Vanina Romanello

Fibroblast growth factor 21 controls mitophagy and muscle mass

Background
Skeletal muscle is a plastic tissue that adapts to changes in exercise, nutrition, and stress by secreting myokines and myometabolites. These muscle-secreted factors have autocrine, paracrine, and endocrine effects, contributing to whole body homeostasis. Muscle dysfunction in aging sarcopenia, cancer cachexia, and diabetes is tightly correlated with the disruption of the physiological homeostasis at the whole body level. The expression levels of the myokine fibroblast growth factor 21 (FGF21) are very low in normal healthy muscles. However, fasting, ER stress, mitochondrial myopathies, and metabolic disorders induce its release from muscles. Although our understanding of the systemic effects of muscle-derived FGF21 is exponentially increasing, the direct contribution of FGF21 to muscle function has not been investigated yet.
Methods
Muscle-specific FGF21 knockout mice were generated to investigate the consequences of FGF21 deletion concerning skeletal muscle mass and force. To identify the mechanisms underlying FGF21-dependent adaptations in skeletal muscle during starvation, the study was performed on muscles collected from both fed and fasted adult mice. In vivo overexpression of FGF21 was performed in skeletal muscle to assess whether FGF21 is sufficient per se to induce muscle atrophy.
Results
We show that FGF21 does not contribute to muscle homeostasis in basal conditions in terms of fibre type distribution, fibre size, and muscle force. In contrast, FGF21 is required for fasting-induced muscle atrophy and weakness. The mass of isolated muscles from control-fasted mice was reduced by 15–25% (P < 0.05) compared with fed control mice. FGF21-null muscles, however, were significantly protected from muscle loss and weakness during fasting. Such important protection is due to the maintenance of protein synthesis rate in knockout muscles during fasting compared with a 70% reduction in control-fasted muscles (P < 0.01), together with a significant reduction of the mitophagy flux via the regulation of the mitochondrial protein Bnip3. The contribution of FGF21 to the atrophy programme was supported by in vivo FGF21 overexpression in muscles, which was sufficient to induce autophagy and muscle loss by 15% (P < 0.05). Bnip3 inhibition protected against FGF21-dependent muscle wasting in adult animals (P < 0.05).
Conclusions
FGF21 is a novel player in the regulation of muscle mass that requires the mitophagy protein Bnip3.

Oost, L. J., Kustermann, M., Armani, A., Blaauw, B., and Romanello, V. ( 2019) Fibroblast growth factor 21 controls mitophagy and muscle mass. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12409.

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     Article first published online:  18 March 2019 

Peng Zhang, Jian He, Fei Wang, Jing Gong, Lu Wang, Qian Wu, Wenjiong Li, Hongju Liu, Jing Wang, Kunshan Zhang, Mao Li, Xusheng Huang, Chuanqiang Pu, Ying Li, Fengjie Jiang, Fudi Wang, Junxia Min, Xiaoping Chen

Hemojuvelin is a novel suppressor for Duchenne muscular dystrophy and age-related muscle wasting

Background
Muscle wasting occurs in response to various physiological and pathological conditions, including ageing and Duchenne muscular dystrophy (DMD). Transforming growth factor-ß1 (TGF-ß1) contributes to muscle pathogenesis in elderly people and DMD patients; inhibition of TGF-ß1 signalling is a promising therapeutic strategy for muscle-wasting disorders. Hemojuvelin (HJV or Hjv as the murine homologue) is a membrane-bound protein that is highly expressed in skeletal muscle, heart, and liver. In hepatic cells, Hjv acts as a coreceptor for bone morphogenetic protein, a TGF-ß subfamily member. The aim of this study was to investigate whether Hjv plays an essential role in muscle physiological and pathophysiological processes by acting as a coreceptor for TGF-ß1 signalling.
Methods
Conventional and conditional Hjv knockout mice as well as mdx and aged mice transfected with Hjv overexpression vector were used to study the role of Hjv in muscle physiology and pathophysiology. qRT-PCR, western blotting, and immunohistochemistry examinations were conducted to evaluate gene, protein, and structural changes in vivo and in vitro. Exercise endurance was determined using treadmill running test, and muscle force was detected by an isometric transducer. RNA interference, immunoprecipitation, and dual-luciferase reporter assays were utilized to explore the mechanism by which Hjv regulates TGF-ß1 signalling in skeletal muscle.
Results
Conventional and conditional Hjv knockout mice displayed muscle atrophy, fibrosis, reduced running endurance, and muscle force. HJV was significantly down-regulated in the muscles of DMD patients (n = 3, mean age: 11.7 ± 5.7 years) and mdx mice as well as in those of aged humans (n = 10, 20% women, mean age: 75.1 ± 9.5 years) and mice. Overexpression of Hjv rescued dystrophic and age-related muscle wasting. Unlike its function in hepatic cells, the bone morphogenetic protein downstream phosphorylated p-Smad1/5/8 signalling pathway was unchanged, but TGF-ß1, TGF-ß receptor II (TßRII), and p-Smad2/3 expression were increased in Hjv-deficient muscles. Mechanistically, loss of Hjv promoted activation of Smad3 signalling induced by TGF-ß1, whereas Hjv overexpression inhibited TGF-ß1/Smad3 signalling by directly interacting with TßRII on the muscle membrane.
Conclusions
Our findings identify an unrecognized role of HJV in skeletal muscle by regulating TGF-ß1/Smad3 signalling as a coreceptor for TßRII. Unlike the TGF-ß1/Smad3 pathway, HJV could be a reliable drug target as its expression is not widespread. Novel therapeutic strategies could potentially be devised to interfere only with the muscle function of HJV to treat DMD and age-related muscle wasting.

Zhang, P., He, J., Wang, F., Gong, J., Wang, L., Wu, Q., Li, W., Liu, H., Wang, J., Zhang, K., Li, M., Huang, X., Pu, C., Li, Y., Jiang, F., Wang, F., Min, J., and Chen, X. ( 2019) Hemojuvelin is a novel suppressor for Duchenne muscular dystrophy and age-related muscle wasting. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12414.

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     Article first published online:  15 March 2019 

Hyun Su Kim, Young Cheol Yoon, Byung-Ok Choi, Wook Jin, Jang Gyu Cha

Muscle fat quantification using magnetic resonance imaging: case–control study of Charcot–Marie–Tooth disease patients and volunteers
Background
This study aimed to evaluate the potential value of 3D multiple gradient echo Dixon-based magnetic resonance imaging (MRI) sequence as a tool for thigh intramuscular fat quantification in Charcot–Marie–Tooth disease (CMT) patients.
Methods
A prospective comparison study comprising 18 CMT patients and 18 age/sex-matched volunteers was performed. MRI including 3D multiple gradient echo Dixon-based imaging was performed for each subject. Region of interest analyses were performed at the upper and lower third of both thighs. The two-sample t-test or Wilcoxon rank sum test was used for intergroup comparison of the mean muscle fat fraction. Intraclass correlation coefficients were used to evaluate the interobserver agreement and test–retest reproducibility. Semiquantitive analysis using the Goutallier classification (Grades 0–4) was performed on T1-weighted images in upper thigh muscles. For Goutallier Grade 0 muscles, comparison of the mean intramuscular fat fraction between volunteers and CMT patients was performed.
Results
The interobserver agreements were excellent for all measurements (intraclass correlation coefficients > 0.8). Mean muscle fat fractions were significantly higher in all the measured muscles of CMT patients (P < 0.05) except in the adductor magnus in the upper thigh (P = 0.109). Goutallier Grade 0 muscles of the CMT patients showed a significantly higher mean fat fraction compared with that of the volunteers (P < 0.05).
Conclusions
3D multiple gradient echo Dixon-based MRI is a reproducible and sensitive technique which can reveal a significant difference in the fat fraction of thigh muscle, including comparison between Goutallier Grade 0 muscles, between CMT patients and volunteers.

Kim, H. S., Yoon, Y. C., Choi, B.-O., Jin, W., and Cha, J. G. ( 2019) Muscle fat quantification using magnetic resonance imaging: case–control study of Charcot–Marie–Tooth disease patients and volunteers. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12415.

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     Article first published online:  13 March 2019 

David P.J. van Dijk, Astrid M.H. Horstman, Joey S.J. Smeets, Marcel den Dulk, Heike I. Grabsch, Cornelis H.C. Dejong, Sander S. Rensen, Steven W.M. Olde, Damink Luc J.C. van Loon

Tumour-specific and organ-specific protein synthesis rates in patients with pancreatic cancer

Background
Living tissues maintain a fine balance between protein synthesis and protein breakdown rates. Animal studies indicate that protein synthesis rates are higher in organs when compared with skeletal muscle tissue. As such, organ and tumour protein synthesis could have major effects on whole-body protein metabolism in wasting disorders such as cancer cachexia. We aimed to assess protein synthesis rates in pancreatic tumour tissue and healthy pancreas, liver, and skeletal muscle tissue in vivo in humans.
Methods
In eight patients with pancreatic cancer undergoing pancreaticoduodenectomy, primed continuous infusions with L-[ring-13C6]phenylalanine and L-[3,5-2H2]tyrosine were started prior to surgery and continued throughout the surgical procedures. During surgery, plasma samples and biopsies from the pancreas, pancreatic tumour, liver, and vastus lateralis muscle were taken. Post-absorptive fractional protein synthesis rates were determined by measuring incorporation of labelled L-[ring-13C6]phenylalanine in tissue protein using the weighed plasma L-[ring-13C6]phenylalanine enrichments as the precursor pool.
Results
Five male patients and three female patients with a mean age of 67 ± 2 years were included into this study. Plasma L-[ring-13C6]phenylalanine enrichments (6–9 mole per cent excess) did not change during surgery (P = 0.60). Pancreatic tumour protein synthesis rates were 2.6-fold lower than surrounding pancreatic tissue protein synthesis rates (0.268 ± 0.053 vs. 0.694 ± 0.228%/h, respectively; P = 0.028) and 1.7-fold lower than liver protein synthesis rates (0.268 ± 0.053 vs. 0.448 ± 0.043%/h, respectively; P = 0.046). Among healthy organ samples, protein synthesis rates were 20-fold and 13-fold higher in pancreas and liver, respectively, compared with skeletal muscle tissue (0.694 ± 0.228 and 0.448 ± 0.043 vs. 0.035 ± 0.005%/h, respectively; P < 0.05).
Conclusions
Liver and pancreas tissue protein synthesis rates are higher when compared with pancreatic tumour and skeletal muscle tissue protein synthesis rates and can, therefore, strongly impact whole-body protein metabolism in vivo in humans.

Dijk, D. P. J., Horstman, A. M. H., Smeets, J. S. J., Dulk, M., Grabsch, H. I., Dejong, C. H. C., Rensen, S. S., Olde Damink, S. W. M., and Loon, L. J. C. ( 2019) Tumour-specific and organ-specific protein synthesis rates in patients with pancreatic cancer. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12419.

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     Article first published online:  06 March 2019

Taimoor H. Qazi, Georg N. Duda, Melanie J. Ort, Carsten Perka, Sven Geissler, Tobias Winkler

Cell therapy to improve regeneration of skeletal muscle injuries
Diseases that jeopardize the musculoskeletal system and cause chronic impairment are prevalent throughout the Western world. In Germany alone, ~1.8 million patients suffer from these diseases annually, and medical expenses have been reported to reach 34.2bn Euros. Although musculoskeletal disorders are seldom fatal, they compromise quality of life and diminish functional capacity. For example, musculoskeletal disorders incur an annual loss of over 0.8 million workforce years to the German economy. Among these diseases, traumatic skeletal muscle injuries are especially problematic because they can occur owing to a variety of causes and are very challenging to treat. In contrast to chronic muscle diseases such as dystrophy, sarcopenia, or cachexia, traumatic muscle injuries inflict damage to localized muscle groups. Although minor muscle trauma heals without severe consequences, no reliable clinical strategy exists to prevent excessive fibrosis or fatty degeneration, both of which occur after severe traumatic injury and contribute to muscle degeneration and dysfunction. Of the many proposed strategies, cell-based approaches have shown the most promising results in numerous pre-clinical studies and have demonstrated success in the handful of clinical trials performed so far. A number of myogenic and non-myogenic cell types benefit muscle healing, either by directly participating in new tissue formation or by stimulating the endogenous processes of muscle repair. These cell types operate via distinct modes of action, and they demonstrate varying levels of feasibility for muscle regeneration depending, to an extent, on the muscle injury model used. While in some models the injury naturally resolves over time, other models have been developed to recapitulate the peculiarities of real-life injuries and therefore mimic the structural and functional impairment observed in humans. Existing limitations of cell therapy approaches include issues related to autologous harvesting, expansion and sorting protocols, optimal dosage, and viability after transplantation. Several clinical trials have been performed to treat skeletal muscle injuries using myogenic progenitor cells or multipotent stromal cells, with promising outcomes. Recent improvements in our understanding of cell behaviour and the mechanistic basis for their modes of action have led to a new paradigm in cell therapies where physical, chemical, and signalling cues presented through biomaterials can instruct cells and enhance their regenerative capacity. Altogether, these studies and experiences provide a positive outlook on future opportunities towards innovative cell-based solutions for treating traumatic muscle injuries—a so far unmet clinical need.

Qazi, T. H., Duda, G. N., Ort, M. J., Perka, C., Geissler, S., and Winkler, T. (2019) Cell therapy to improve regeneration of skeletal muscle injuries. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12416.

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     Article first published online:  04 March 2019 

Saunjoo L. Yoon, Jung A Kim, Debra Lynch Kelly, Debra Lyon, Thomas J. George Jr.

Predicting unintentional weight loss in patients with gastrointestinal cancer
Background
Unintentional weight loss is a major problem for patients with gastrointestinal (GI) cancers because it affects treatment, survival outcomes, and quality of life. To date, little is known about the trajectory of weight loss and the relationship between baseline body mass index (BMI), location of the cancer, and outcomes. The aims of this study were to investigate patterns of weight loss over time in patients with GI cancer according to BMI groups (low, normal, and high) and location of cancer.
Methods
We examined de-identified electronic medical record data of 801 adults (>21 years) with GI cancer using ICD-9 codes (150–159). Descriptive statistics and linear mixed models were used to examine unintentional weight loss over time by BMI group (low, normal, and high) and to determine the effect of primary cancer site and patient characteristics on weight loss.
Results
The mean age of patients was 66.5 ± 11.9 years (21–95 years), with 58% male and 86% White. Mean weight loss over 3 years was 21.39 kg. At the first observation point, 7.8% were in the low BMI group, 30.1% were in the normal, and 62% were in the high group. At the end of observation, a majority of deaths (35.5%) occurred in the low BMI group (BMI < 20 kg/m2). Significant weight loss was observed in patients with gastric (t = -5.11, P < 0.001), oesophageal (t = -4.18, P < 0.001), and pancreatic (35.8%, t = -3.58, P < 0.001) cancers. Predictors of weight change were gender (F = 64.93, P < 0.001), cancer stage (F = 7.28, P < 0.001), and site by days (F = 8.24, P < 0.001). Weight loss rates were similar among the three BMI groups, but patterns were different based on primary cancer type as a function of days within each group.
Conclusions
Weight loss in patients with GI cancers has implications for survival. Patients with upper GI cancers experienced more weight loss and decreased survival rates compared with patients with lower GI cancers. Patients with a combination of upper GI cancer (oesophagogastric or pancreatic) and low baseline BMI had the fewest survival days and worst patient outcomes. Early intervention for weight management plays a critical role for improving the health outcomes and fatality rates of these patients.

Yoon, S. L., Kim, J. A., Kelly, D. L., Lyon, D., and George, T. J. Jr. (2019) Predicting unintentional weight loss in patients with gastrointestinal cancer. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12398.

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     Article first published online:  24 January 2019

Nadja Scherbakov, Charlotte Pietrock, Anja Sandek, Nicole Ebner, Miroslava Valentova, Jochen Springer, Joerg C. Schefold, Stephan von Haehling, Stefan D. Anker, Kristina Norman, Karl Georg Haeusler, Wolfram Doehner

Body weight changes and incidence of cachexia after stroke
Background
Body weight loss is a frequent complication after stroke, and its adverse effect on clinical outcome has been shown in several clinical trials. The purpose of this prospective longitudinal single‐centre observational study was to investigate dynamical changes of body composition and body weight after ischemic stroke and an association with functional outcome.
Methods
Sixty‐seven consecutive patients (age 69 ± 11 years, body mass index 27.0 ± 4.1 kg/m2, 42% female patient, mean ± SD) with acute ischemic stroke with mild to moderate neurological deficit (National Institute of Health Stroke Scale median 4, ranged 0–12) were analysed in the acute phase (4 ± 2 days) and at 12 months (389 ± 26 days) follow‐up. Body composition was examined by dual energy X‐ray absorptiometry. Cachexia was defined according to the consensus definition by body weight loss ≥5% within 1 year and additional clinical signs. Lean tissue wasting was considered if a ratio of upper and lower limbs lean mass sum to squared height (kg/m2) was ≤5.45 kg/m2 for female patient and ≤7.25 kg/m2 for male patient.
Results
According to the body weight changes after 12 months, 42 (63%) patients had weight gain or stable weight, 11 (16%) patients had moderate weight loss, and 14 (21%) patients became cachectic. A relative decline of 19% of fat tissue and 6.5% of lean tissue was observed in cachectic patients, while no changes of lean tissue were observed in non‐cachectic patients after 12 months. The modified Rankin Scale was 48% higher (2.1 ± 1.6, P < 0.05), Barthel Index was 22% lower (71 ± 39, P < 0.01), and handgrip strength was 34% lower (21.9 ± 13.0, P < 0.05) in cachectic compared to non‐cachectic patients after 12 months.
The low physical performance if defined by Barthel Index <60 points was linked to the lean tissue wasting (OR 44.8, P < 0.01), presence of cachexia (OR 20.8, P < 0.01), and low body mass index <25 kg/m2 (OR 11.5, P < 0.05). After adjustment for cofounders, lean tissue wasting remained independently associated with the low physical performance at 12 months follow‐up (OR 137.9, P < 0.05).
Conclusions
In this cohort study, every fifth patient with ischemic stroke fulfilled the criteria of cachexia within 12 months after index event. The incidence of cachexia was 21%. Cachectic patients showed the lowest functional and physical capacity.

Scherbakov, N., Pietrock, C., Sandek, A., Ebner, N., Valentova, M., Springer, J., Schefold, J. C., von Haehling, S., Anker, S. D., Norman, K., Haeusler, K. G., and Doehner, W. (2019) Body weight changes and incidence of cachexia after stroke. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12400.

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