Article first published online:  30 November 2018

Robert H. Schüchen, Martin Mücke, Milka Marinova, Dmitrij Kravchenko, Winfried Häuser, Lukas Radbruch, Rupert Conrad

Cellular and molecular mechanisms of sarcopenia: the S100B perspective
Primary sarcopenia is a condition of reduced skeletal muscle mass and strength, reduced agility, and increased fatigability and risk of bone fractures characteristic of aged, otherwise healthy people. The pathogenesis of primary sarcopenia is not completely understood. Herein, we review the essentials of the cellular and molecular mechanisms of skeletal mass maintenance; the alterations of myofiber metabolism and deranged properties of muscle satellite cells (the adult stem cells of skeletal muscles) that underpin the pathophysiology of primary sarcopenia; the role of the Ca2+-sensor protein, S100B, as an intracellular factor and an extracellular signal regulating cell functions; and the functional role of S100B in muscle tissue. Lastly, building on recent results pointing to S100B as to a molecular determinant of myoblast–brown adipocyte transition, we propose S100B as a transducer of the deleterious effects of accumulation of reactive oxygen species in myoblasts and, potentially, myofibers concurring to the pathophysiology of sarcopenia.

Riuzzi, F., Sorci, G., Arcuri, C., Giambanco, I., Bellezza, I., Minelli, A., and Donato, R. (2018) Cellular and molecular mechanisms of sarcopenia: the S100B perspective. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12363.

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     Article first published online:  22 November 2018

William A. Cuellar, Leigh Blizzard, Julie A. Hides, Michele L. Callisaya, Graeme Jones, Flavia Cicuttini, Anita E. Wluka, Changhai Ding, Tania M. Winzenberg

Vitamin D supplements for trunk muscle morphology in older adults: secondary analysis of a randomized controlled trial
Background
The effect of vitamin D supplementation on postural muscles of the trunk is of particular interest because low 25-hydroxyvitamin D [25(OH) D] levels are associated with decreased postural balance and increased risk of falls. Understanding the role of vitamin D supplementation plays in trunk muscle function of older adults is necessary, as this is a potentially modifiable factor to improve postural muscle function and decrease the risk of falling of older adults. The objective of this randomized controlled trial was to evaluate the effect of 12 months of vitamin D supplementation compared with placebo, on morphology and function of the trunk muscles of adults aged 50 to 79 years with low serum 25(OH) D levels.
Methods
This was a secondary analysis of a randomized, placebo-controlled, and double-blind clinical trial conducted between June 2010 and December 2013 in Tasmania, Australia. The clinical trial was registered with the Australian New Zealand clinical trial registration agency, ClinicalTrials.gov identifier: NCT01176344; Australian New Zealand Clinical Trials Registry: ACTRN 12610000495022. Participants were aged 50–79 years with ongoing symptoms of knee osteoarthritis and with low serum [25(OH) D] (12.5 to 60 nmol/L, 5.2 to 24 ng/mL). Participants were randomly assigned to either monthly 50 000 IU oral vitamin D3 (n = 104) or an identical placebo (n = 113) for 24 months as per clinical trial protocol. The primary outcomes in this pre-specified secondary analysis were between-group differences in change in size of rectus abdominis, transversus abdominis, internal oblique, external oblique, and lumbar multifidus muscles and function (assessed by change in thickness on contraction) of these muscles (excepting rectus abdominis) from baseline to 12 months. Muscle size was assessed using ultrasound imaging.
Results
Of 217 participants (mean age 63 years, 48% women), 186 (85.7%) completed the study. There were no significant between-group differences in change in size or function of the abdominal or multifidus muscles after 12 months of vitamin D supplementation.
Conclusions
A monthly dose of 50 000 IU of vitamin D3 alone for 12 months does not affect the size or ability to contract trunk muscles of independent community-dwelling older adults with symptomatic knee osteoarthritis and low serum 25(OH) D levels regardless of body mass index status or degree of vitamin D deficiency. An effect of vitamin D supplementation on other aspects of trunk muscle function such as strength, power, or physical function cannot be ruled out.

Cuellar, W. A., Blizzard, L., Hides, J. A., Callisaya, M. L., Jones, G., Cicuttini, F., Wluka, A. E., Ding, C., and Winzenberg, T. M. (2018) Vitamin D supplements for trunk muscle morphology in older adults: secondary analysis of a randomized controlled trial. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12364.

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     Article first published online:  21 November 2018

Qing Zhang, Agnès Duplany, Vincent Moncollin, Sandrine Mouradian, Evelyne Goillot, Laetitia Mazelin, Karine Gauthier, Nathalie Streichenberger, Céline Angleraux, Jie Chen, Shuzhe Ding, Laurent Schaeffer, Yann-Gaël Gangloff

Lack of muscle mTOR kinase activity causes early onset myopathy and compromises whole-body homeostasis
Background
The protein kinase mechanistic target of rapamycin (mTOR) controls cellular growth and metabolism. Although balanced mTOR signalling is required for proper muscle homeostasis, partial mTOR inhibition by rapamycin has beneficial effects on various muscle disorders and age-related pathologies. Besides, more potent mTOR inhibitors targeting mTOR catalytic activity have been developed and are in clinical trials. However, the physiological impact of loss of mTOR catalytic activity in skeletal muscle is currently unknown.
Methods
We have generated the mTORmKOKI mouse model in which conditional loss of mTOR is concomitant with expression of kinase inactive mTOR in skeletal muscle. We performed a comparative phenotypic and biochemical analysis of mTORmKOKI mutant animals with muscle-specific mTOR knockout (mTORmKO) littermates.
Results
In striking contrast with mTORmKO littermates, mTORmKOKI mice developed an early onset rapidly progressive myopathy causing juvenile lethality. More than 50% mTORmKOKI mice died before 8 weeks of age, and none survived more than 12 weeks, while mTORmKO mice died around 7 months of age. The growth rate of mTORmKOKI mice declined beyond 1 week of age, and the animals showed profound alterations in body composition at 4 weeks of age. At this age, their body weight was 64% that of mTORmKO mice (P < 0.001) due to significant reduction in lean and fat mass. The mass of isolated muscles from mTORmKOKI mice was remarkably decreased by 38–56% (P < 0.001) as compared with that from mTORmKO mice. Histopathological analysis further revealed exacerbated dystrophic features and metabolic alterations in both slow/oxidative and fast/glycolytic muscles from mTORmKOKI mice. We show that the severity of the mTORmKOKI as compared with the mild mTORmKO phenotype is due to more robust suppression of muscle mTORC1 signalling leading to stronger alterations in protein synthesis, oxidative metabolism, and autophagy. This was accompanied with stronger feedback activation of PKB/Akt and dramatic down-regulation of glycogen phosphorylase expression (0.16-fold in tibialis anterior muscle, P < 0.01), thus causing features of glycogen storage disease type V.
Conclusions
Our study demonstrates a critical role for muscle mTOR catalytic activity in the regulation of whole-body growth and homeostasis. We suggest that skeletal muscle targeting with mTOR catalytic inhibitors may have detrimental effects. The mTORmKOKI mutant mouse provides an animal model for the pathophysiological understanding of muscle mTOR activity inhibition as well as for mechanistic investigation of the influence of skeletal muscle perturbations on whole-body homeostasis.

Zhang, Q., Duplany, A., Moncollin, V., Mouradian, S., Goillot, E., Mazelin, L., Gauthier, K., Streichenberger, N., Angleraux, C., Chen, J., Ding, S., Schaeffer, L., and Gangloff, Y.-G. (2018) Lack of muscle mTOR kinase activity causes early onset myopathy and compromises whole-body homeostasis. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12336.

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     Article first published online:  20 November 2018

Ross D. Dolan, Arwa S. Almasaudi, Ly B. Dieu, Paul G. Horgan, Stephen T. McSorley, Donald C. McMillan

The relationship between computed tomography-derived body composition, systemic inflammatory response, and survival in patients undergoing surgery for colorectal cancer
Introduction
Colorectal cancer is the fourth leading cause of cancer mortality in developed countries. There is evidence supporting a disproportionate loss of skeletal muscle as an independent prognostic factor. The importance of the systemic inflammatory response as a unifying mechanism for specific loss of skeletal muscle mass in patients with cancer is increasingly recognized. The aim of the present study was to delineate the relationship between the systemic inflammatory response, skeletal muscle index (SMI), skeletal muscle density (SMD), and overall survival in patients with colorectal cancer.
Materials and methods
The study included 650 patients with primary operable colorectal cancer. Computed tomography scans were used to define the presence of visceral obesity, sarcopenia (low SMI), and myosteatosis (low SMD). Tumour and patient characteristics were recorded. Survival analysis was carried out using univariate and multivariate Cox regression.
Results
A total of 650 patients (354 men and 296 women) were included. The majority of patients were over 65 years of age (64%) and overweight or obese (68%). On univariate survival analysis, age, ASA, TNM stage, modified Glasgow Prognostic Score (mGPS), body mass index, subcutaneous fat index, visceral obesity, SMI, and SMD were significantly associated with overall survival (all P < 0.05). A low SMI and SMD were significantly associated with an elevated mGPS (<0.05). On multivariate analysis, SMI (Martin) [hazard ratio (HR) 1.50, 95% confidence interval (CI) 1.04–2.18, P = 0.031], SMD (Xiao) (HR 1.42, 95% CI 0.98–2.05, P = 0.061), and mGPS (HR 1.44, 95% CI 1.15–1.79, P = 0.001) were independently associated with overall survival. SMD but not SMI was significantly associated with ASA (P < 0.001).
Conclusions
This study delineates the relationship between the loss of quantity and quality of skeletal muscle mass, the systemic inflammatory response, and survival in patients with operable colorectal cancer.

Dolan, R. D., Almasaudi, A. S., Dieu, L. B., Horgan, P. G., McSorley, S. T., and McMillan, D. C. (2018) The relationship between computed tomography-derived body composition, systemic inflammatory response, and survival in patients undergoing surgery for colorectal cancer. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12357.

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     Article first published online:  5 November 2018

Maria Papageorgiou, Thozhukat Sathyapalan, Rudolph Schutte

Muscle mass measures and incident osteoporosis in a large cohort of postmenopausal women
Background
Despite several muscle mass measures being used in the current definitions of sarcopenia, their usefulness is uncertain because of limited data on their association with health outcomes. The aim of the study was to compare the performance of different muscle mass measures for predicting incident osteoporosis in postmenopausal women.
Methods
This study included data from 149 166 participants (aged 60.3 ± 5.5 years) as part of the UK Biobank cohort. Body composition was assessed using bioelectrical impedance. The muscle mass measures included were total body skeletal muscle mass (SMM) and appendicular SMM (aSMM) divided by height squared (ht2), derived residuals, SMM, SMM adjusted for body mass (SMM/bm × 100), and aSMM normalized for body mass index (aSMM/BMI). Diagnoses of the events were confirmed by primary care physicians and coded according to the World Health Organization's International Classification of Diseases 10th Revision (ICD‐10: M80‐M82).
Results
Over a median follow‐up of 6.75 (5th to 95th percentile interval, 1.53 to 8.37) years, 394 newly diagnosed cases of osteoporosis occurred, with 40 (10.2%) cases being associated with a pathological fracture. SMM/ht2, aSMM/ht2 residual, and SMM were lower in postmenopausal women with osteoporosis compared with women without (all P < 0.0001), while SMM/bm × 100 (P = 0.003), but not aSMM/BMI (P = 0.59), was higher in the osteoporosis group. The unadjusted rates of osteoporosis increased with decreasing quintiles for SMM/ht2, aSMM/ht2, residuals, and SMM (all P trend <0.0001), while the incidence of osteoporosis increased with increasing SMM/bm × 100 (P trend =0.001), but not for aSMM/BMI (P = 0.45). After minimally adjusting for age and after full adjustment, SMM/ht2, aSMM/ht2, and SMM were the only measure that consistently predicted osteoporosis in the total group of postmenopausal women [hazard ratio (HR) 0.65–0.67, all P ≤ 0.0001], in lean women (HR 0.62–0.68; all P ≤ 0.001), and women with increased adiposity (HR 0.64–0.68; all P ≤ 0.01). In fully adjusted models, the changes in the R2 statistic were 13.4%, 11.6%, and 15.3% for the SMM/ht2 (aSMM/ht2), residual, and SMM, but only 4.9% and 1.3% for SMM/bm × 100 and aSMM/BMI.
Conclusions
Muscle mass measures adjusted for height only (SMM/ht2, aSMM/ht2) appear to be better muscle‐relevant risk factors for incident osteoporosis in postmenopausal women, including when stratified into lean participants and participants with increased adiposity.

Papageorgiou, M., Sathyapalan, T., and Schutte, R. (2018) Muscle mass measures and incident osteoporosis in a large cohort of postmenopausal women. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12359.

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     Article first published online:  31 October 2018

Huang‐Jen Chen, Ching‐Chia Wang, Ding‐Cheng Chan, Chen‐Yuan Chiu, Rong‐Sen Yang, Shing‐Hwa Liu

Adverse effects of acrolein, a ubiquitous environmental toxicant, on muscle regeneration and mass
Background
Acrolein is an extremely electrophilic aldehyde. Increased urinary acrolein adducts have been found in type 2 diabetic patients and people with a smoking habit. The increased blood acrolein was shown in patients who received the cancer drug cyclophosphamide. Both diabetes and smoking are risk factors for skeletal muscle wasting or atrophy. Acrolein has been found to induce myotube atrophy in vitro. The in vitro and in vivo effects and mechanisms of acrolein on myogenesis and the in vivo effect of acrolein on muscle wasting still remain unclear.
Methods
C2C12 myoblasts were used to assess the effects of low‐dose acrolein (0.125–1 μM) on myogenesis in vitro. Mice were exposed daily to acrolein in distilled water by oral administration (2.5 and 5 mg/kg) for 4 weeks with or without glycerol‐induced muscle injury to investigate the effects of acrolein on muscle wasting and regeneration.
Results
Non‐cytotoxic‐concentration acrolein dose dependently inhibited myogenic differentiation in myoblasts (myotube formation inhibition: 0.5 and 1 μM, 66.25% and 46.25% control, respectively, n = 4, P < 0.05). The protein expression for myogenesis‐related signalling molecules (myogenin and phosphorylated Akt: 0.5 and 1 μM, 85.15% and 51.52% control and 62.63% and 56.57% control, respectively, n = 4, P < 0.05) and myosin heavy chain (MHC: 0.5 and 1 μM, 63.64% and 52.53% control, n = 4, P < 0.05) were decreased in acrolein‐treated myoblasts. Over‐expression of the constitutively active form of Akt in myoblasts during differentiation prevented the inhibitory effects of acrolein (1 μM) on myogenesis (MHC and myogenin protein expression: acrolein with or without constitutively active Akt, 64.65% and 105.21% control and 69.14% and 102.02% control, respectively, n = 5, P < 0.05). Oral administration of acrolein for 4 weeks reduced muscle weights (5 mg/kg/day: 65.52% control, n = 6, P < 0.05) and cross‐sectional area of myofibers in soleus muscles (5 mg/kg/day: 79.92% control, n = 6, P < 0.05) with an up‐regulation of atrogin‐1 and a down‐regulation of phosphorylated Akt protein expressions. Acrolein retarded soleus muscle regeneration in a glycerol‐induced muscle regeneration mouse model (5 mg/kg/day: 49.29% control, n = 4, P < 0.05). Acrolein exposure reduced muscle endurance during rotarod fatigue performance in mice with or without glycerol‐induced muscle injury (5 mg/kg/day without glycerol: 30.43% control, n = 4, P < 0.05). Accumulation of acrolein protein adducts could be detected in the soleus muscles of acrolein‐treated mice.
Conclusions
Low‐dose acrolein significantly inhibited myogenic differentiation in vitro, which might be through inhibition of Akt signalling. Acrolein induced muscle wasting and retarded muscle regeneration in mice. These results suggest that acrolein may be a risk factor for myogenesis and disease‐related myopathy.

Chen, H.‐J., Wang, C.‐C., Chan, D.‐C., Chiu, C.‐Y., Yang, R.‐S., and Liu, S.‐H. (2018) Adverse effects of acrolein, a ubiquitous environmental toxicant, on muscle regeneration and mass. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12362.

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     Article first published online:  31 October 2018

David P.J. van Dijk, Matthew Krill, Farshad Farshidfar, Ting Li, Sander S. Rensen, Steven W.M. Olde Damink, Elijah Dixon, Francis R. Sutherland, Chad G. Ball, Vera C. Mazurak, Vickie E. Baracos; Oliver F. Bathe

Host phenotype is associated with reduced survival independent of tumour biology in patients with colorectal liver metastases
Background
Most prognostic scoring systems for colorectal liver metastases (CRLMs) account for factors related to tumour biology. Little is known about the effects of the host phenotype to the tumour. Our objective was to delineate the relationship of systemic inflammation and body composition features [i.e. low skeletal muscle mass (sarcopenia) and low visceral adipose tissue (VAT)], two well‐described host phenotypes in cancer.
Methods
Clinical data and pre‐operative blood samples were collected from 99 patients who underwent resection of CRLM. Pre‐operative computed tomography scans were available for 97 patients; body composition was analysed at the L3 level, stratified for sex and age. Clinicopathological variables, serum C‐reactive protein (CRP), and various body composition variables were evaluated. Overall survival was evaluated as a function of these same variables in multivariate Cox regression analysis.
Results
Skeletal muscle was significantly correlated with VAT (r = 0.46, P < 0.001). Of patients with sarcopenia, 35 (65%) also had low VAT. C‐reactive protein was elevated (≥5 mg/mL) in 42 patients (43.3%). Elevated CRP was more common in patients with sarcopenia (73.8% vs. 51.1%, P = 0.029). The most significant prognostic factors were the coincidence of elevated CRP and adverse body composition features (sarcopenia and/or low VAT; hazard ratio 4.3, 95% confidence interval 1.5–13.0, P = 0.008), as well as Fong clinical prognostic score (hazard ratio 2.9, 95% confidence interval 1.5–5.5, P = 0.002).
Conclusions
Body composition in patients with CRLM is not directly linked to the presence of systemic inflammation. However, when systemic inflammation coincides with sarcopenia and/or low VAT, prognosis is adversely affected, independent of the Fong clinical prognostic score.

van Dijk, D. P. J., Krill, M., Farshidfar, F., Li, T., Rensen, S. S., Olde Damink, S. W. M., Dixon, E., Sutherland, F. R., Ball, C. G., Mazurak, V. C., Baracos, V. E., and Bathe, O. F. (2018) Host phenotype is associated with reduced survival independent of tumour biology in patients with colorectal liver metastases. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12358.

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     Article first published online:  30 October 2018

Roland Veltkamp, Stefan Uhlmann, Marilena Marinescu, Carsten Sticht,Daniel Finke, Norbert Gretz, Herrmann‐Josef Gröne, Hugo A. Katus, Johannes Backs, Lorenz H. Lehmann

Experimental ischaemic stroke induces transient cardiac atrophy and dysfunction
Background
Stroke can lead to cardiac dysfunction in patients, but the mechanisms underlying the interaction between the injured brain and the heart are poorly understood. The objective of the study is to investigate the effects of experimental murine stroke on cardiac function and molecular signalling in the heart.
Methods and results
Mice were subjected to filament‐induced left middle cerebral artery occlusion for 30 or 60 min or sham surgery and underwent repetitive micro‐echocardiography. Left ventricular contractility was reduced early (24–72 h) but not late (2 months) after brain ischaemia. Cardiac dysfunction was accompanied by a release of high‐sensitive cardiac troponin (hsTNT (ng/ml): d1: 7.0 ± 1.0 vs. 25.0 ± 3.2*; d3: 7.3 ± 1.1 vs. 52.2 ± 16.7*; d14: 5.7 ± 0.8 vs. 5.2 ± 0.3; sham vs. 60 min. MCAO; mean ± SEM; *p < 0.05); reduced heart weight (heart weight/tibia length ratio: d1: 6.9 ± 0.2 vs. 6.4 ± 0.1*; d3: 6.7 ± 0.2 vs. 5.8 ± 0.1*; d14: 6.7 ± 0.2 vs. 6.4 ± 03; sham vs. 60 min. MCAO; mean ± SEM; *p < 0.05); resulting from cardiomyocyte atrophy (cardiomyocyte size: d1: 12.8% ± 0.002**; d3: 13.5% ± 0.002**; 14d: 6.3% ± 0.003*; 60 min. MCAO vs. sham; mean ± SEM; **p < 0.01; *p < 0.05), accompanied by increased atrogin‐1 and the E3 ubiquitin ligase murf‐1. Net norepinephrine but not synthesis was increased, suggesting a reduced norepinephrine release or an increase of norepinephrine re‐uptake, resulting in a functional denervation. Transcriptome analysis in cardiac tissue identified the transcription factor peroxisome proliferator‐activated receptor gamma as a potential mediator of stroke‐induced transcriptional dysregulation involved in cardiac atrophy.
Conclusions
Stroke induces a complex molecular response in the heart muscle with immediate but transient cardiac atrophy and dysfunction.

Veltkamp, R., Uhlmann, S., Marinescu, M., Sticht, C., Finke, D., Gretz, N., Gröne, H.‐J., Katus, H. A., Backs, J., and Lehmann, L. H. (2018) Experimental ischaemic stroke induces transient cardiac atrophy and dysfunction. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12335.

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     Article first published online:  29 October 2018

Brianna Bourgeois, Bo Fan, Neil Johannsen, Maria Cristina Gonzalez, Bennett K. Ng, Markus J. Sommer, John A. Shepherd, Steven B. Heymsfield

Improved strength prediction combining clinically available measures of skeletal muscle mass and quality
Background
Measures of skeletal muscle function decline at a faster rate with ageing than do indices of skeletal muscle mass. These observations have been attributed to age‐related changes in muscle quality, another functional determinant separate from skeletal muscle mass. This study tested the hypothesis that improved predictions of skeletal muscle strength can be accomplished by combining clinically available measures of skeletal muscle mass and quality.
Methods
The participants included 146 healthy adult (age ≥ 18 years, range 18–77 years; X ± SD 47 ± 17 years and body mass index 16.5–51.8 kg/m2; 27.7 ± 6.2 kg/m2) men (n = 60) and women (n = 86) in whom skeletal muscle mass was estimated as appendicular lean soft tissue (LST) measured by dual‐energy X‐ray absorptiometry and skeletal muscle quality as bioimpedance analysis‐derived phase angle and B‐mode‐evaluated echogenicity of mid‐thigh skeletal muscle. Strength of the right leg and both arms was quantified as knee isokinetic extension and handgrip strength using dynamometers. The statistical significance of adding phase angle or echogenicity to strength prediction multiple regression models that included extremity‐specific LST and other covariates (e.g. age and sex) was evaluated to test the study hypothesis.
Results
Right leg LST mass alone was significantly (P < 0.0001) correlated with isokinetic right leg strength (R2 = 0.57). The addition of segmental phase angle measured in the right leg at 50 kHz increased the R2 of this model to 0.66 (P < 0.0001); other phase angle frequencies (5 and 250 kHz) did not contribute significantly to these models. Results were similar for both right and left arm handgrip strength prediction models. Adding age and sex as model covariates increased the R2 values of these models further (e.g. right leg strength model R2 increased to 0.71), but phase angle continued to remain a significant (all P < 0.01) predictor of extremity strength. Similarly, when predicting isokinetic right leg strength, mid‐thigh skeletal muscle echogenicity added significantly (P < 0.0001) to right leg LST, increasing R2 from 0.57 to 0.64; age was a significant (P < 0.0001) covariate in this model, increasing R2 further to 0.68.
Conclusions
The hypothesis of the current study was confirmed, strongly supporting and extending earlier reports by quantifying the combined independent effects of skeletal muscle mass and quality on lower‐body and upper‐body measures of strength. These observations provide a clinically available method for future research aimed at optimizing sarcopenia and frailty risk prediction models.

Bourgeois, B., Fan, B., Johannsen, N., Gonzalez, M. C., Ng, B. K., Sommer, M. J., Shepherd, J. A., and Heymsfield, S. B. (2018) Improved strength prediction combining clinically available measures of skeletal muscle mass and quality. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12353.

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     Article first published online:  29 October 2018

Robert H. Schüchen, Martin Mücke, Milka Marinova, Dmitrij Kravchenko, Winfried Häuser, Lukas Radbruch, Rupert Conrad

Systematic review and meta‐analysis on non‐opioid analgesics in palliative medicine
Non‐opioid analgesics are widely used for pain relief in palliative medicine. However, there is a lack of evidence‐based recommendations addressing the efficacy, tolerability, and safety of non‐opioids in this field. A comprehensive systematic review and meta‐analysis on current evidence can provide a basis for sound recommendations in clinical practice. A database search for controlled trials on the use of non‐opioids in adult palliative patients was performed in Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PsycINFO, and EMBASE from inception to 18 February 2018. Endpoints were pain intensity, opioid‐sparing effects, safety, and quality of life. Studies with similar patients, interventions, and outcomes were included in the meta‐analyses. Our systematic search was able to only identify studies dealing with cancer pain. Of 5991 retrieved studies, 43 could be included (n = 2925 patients). There was no convincing evidence for satisfactory pain relief by acetaminophen alone or in combination with strong opioids. We found substantial evidence of moderate quality for a satisfactory pain relief in cancer by non‐steroidal anti‐inflammatory drugs (NSAIDs), flupirtine, and dipyrone compared with placebo or other analgesics. There was no evidence for a superiority of one specific non‐opioid. There was moderate quality of evidence for a similar pain reduction by NSAIDs in the usual dosage range compared with up to 15 mg of morphine or opioids of equianalgesic potency. The combination of NSAID and step III opioids showed a beneficial effect, without a decreased tolerability. There is scarce evidence concerning the combination of NSAIDs with weak opioids. There are no randomized‐controlled studies on the use of non‐opioids in a wide range of end‐stage diseases except for cancer. Non‐steroidal anti‐inflammatory drugs, flupirtine, and dipyrone can be recommended for the treatment of cancer pain either alone or in combination with strong opioids. The use of acetaminophen in the palliative setting cannot be recommended. Studies are not available for long‐term use. There is a lack of evidence regarding pain treatment by non‐opioids in specific cancer entities.

Schüchen, R. H., Mücke, M., Marinova, M., Kravchenko, D., Häuser, W., Radbruch, L., and Conrad, R. (2018) Systematic review and meta‐analysis on non‐opioid analgesics in palliative medicine. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12352.

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     Article first published online:  25 October 2018

Daryl P. Fields, Brandon M. Roberts, Alec K. Simon, Andrew R. Judge, David D. Fuller, Gordon S. Mitchell

Cancer cachexia impairs neural respiratory drive in hypoxia but not hypercapnia
Background
Cancer cachexia is an insidious process characterized by muscle atrophy with associated motor deficits, including diaphragm weakness and respiratory insufficiency. Although neuropathology contributes to muscle wasting and motor deficits in many clinical disorders, neural involvement in cachexia‐linked respiratory insufficiency has not been explored.
Methods
We first used whole‐body plethysmography to assess ventilatory responses to hypoxic and hypercapnic chemoreflex activation in mice inoculated with the C26 colon adenocarcinoma cell line. Mice were exposed to a sequence of inspired gas mixtures consisting of (i) air, (ii) hypoxia (11% O2) with normocapnia, (iii) hypercapnia (7% CO2) with normoxia, and (iv) combined hypercapnia with hypoxia (i.e. maximal chemoreflex response). We also tested the respiratory neural network directly by recording inspiratory burst output from ligated phrenic nerves, thereby bypassing influences from changes in diaphragm muscle strength, respiratory mechanics, or compensation through recruitment of accessory motor pools.
Results
Cachectic mice demonstrated a significant attenuation of the hypoxic tidal volume (0.26mL±0.01mL vs 0.30mL±0.01mL; p<0.05), breathing frequency (317±10bpm vs 344±6bpm; p<0.05) and phrenic nerve (29.5±2.6% vs 78.8±11.8%; p<0.05) responses. On the other hand, the much larger hypercapnic tidal volume (0.46±0.01mL vs 0.46±0.01mL; p>0.05), breathing frequency (392±5bpm vs 408±5bpm; p>0.05) and phrenic nerve (93.1±8.8% vs 111.1±13.2%; p>0.05) responses were not affected. Further, the concurrent hypercapnia/hypoxia tidal volume (0.45±0.01mL vs 0.45±0.01mL; p>0.05), breathing frequency (395±7bpm vs 400±3bpm; p>0.05), and phrenic nerve (106.8±7.1% vs 147.5±38.8%; p>0.05) responses were not different between C26 cachectic and control mice.
Conclusions
Breathing deficits associated with cancer cachexia are specific to the hypoxic ventilatory response and, thus, reflect disruptions in the hypoxic chemoafferent neural network. Diagnostic techniques that detect decompensation and therapeutic approaches that support the failing hypoxic respiratory response may benefit patients at risk for cancer cachectic‐associated respiratory failure.

Fields, D. P., Roberts, B. M., Simon, A. K., Judge, A. R., Fuller, D. D., and Mitchell, G. S. (2018) Cancer cachexia impairs neural respiratory drive in hypoxia but not hypercapnia. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12348.

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     Article first published online:  18 October 2018

Tateaki Naito Shuichi Mitsunaga Satoru Miura Noriatsu Tatematsu Toshimi Inano Takako Mouri Tetsuya Tsuji Takashi Higashiguchi Akio Inui Taro Okayama Teiko Yamaguchi Ayumu Morikawa Naoharu Mori Toshiaki Takahashi Florian Strasser Katsuhiro Omae Keita Mori Koichi Takayama

Feasibility of early multimodal interventions for elderly patients with advanced pancreatic and non‐small‐cell lung cancer
Background
Combinations of exercise and nutritional interventions might improve the functional prognosis for cachectic cancer patients. However, high attrition and poor compliance with interventions limit their efficacy. We aimed to test the feasibility of the early induction of new multimodal interventions specific for elderly patients with advanced cancer Nutrition and Exercise Treatment for Advanced Cancer (NEXTAC) programme.
Methods
This was a multicentre prospective single‐arm study. We recruited 30 of 46 screened patients aged ≥70 years scheduled to receive first‐line chemotherapy for newly diagnosed, advanced pancreatic, or non‐small‐cell lung cancer. Physical activity was measured using pedometers/accelerometer (Lifecorder®, Suzuken Co., Ltd., Japan). An 8 week educational intervention comprised three exercise and three nutritional sessions. The exercise interventions combined home‐based low‐intensity resistance training and counselling to promote physical activity. Nutritional interventions included standard nutritional counselling and instruction on how to manage symptoms that interfere with patient's appetite and oral intake. Supplements rich in branched‐chain amino acids (Inner Power®, Otsuka Pharmaceutical Co., Ltd., Japan) were provided. The primary endpoint of the study was feasibility, which was defined as the proportion of patients attending ≥4 of six sessions. Secondary endpoints included compliance and safety.
Results
The median patient age was 75 years (range, 70–84). Twelve patients (40%) were cachectic at baseline. Twenty‐nine patients attended ≥4 of the six planned sessions (96.7%, 95% confidence interval, 83.3 to 99.4). One patient dropped out due to deteriorating health status. The median proportion of days of compliance with supplement consumption and exercise performance were 99% and 91%, respectively. Adverse events possibly related to the NEXTAC programme were observed in five patients and included muscle pain (Grade 1 in two patients), arthralgia (Grade 1 in one patient), dyspnoea on exertion (Grade 1 in one patient), and plantar aponeurositis (Grade 1 in one patient).
Conclusions
The early induction of multimodal interventions showed excellent compliance and safety in elderly patients with newly diagnosed pancreatic and non‐small‐cell lung cancer receiving concurrent chemotherapy. We are now conducting a randomized phase II study to measure the impact of these interventions on functional prognosis.

Naito, T., Mitsunaga, S., Miura, S., Tatematsu, N., Inano, T., Mouri, T., Tsuji, T., Higashiguchi, T., Inui, A., Okayama, T., Yamaguchi, T., Morikawa, A., Mori, N., Takahashi, T., Strasser, F., Omae, K., Mori, K., and Takayama, K. (2018) Feasibility of early multimodal interventions for elderly patients with advanced pancreatic and non‐small‐cell lung cancer. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12351.

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     Article first published online:  18 October 2018

Francesca Riuzzi, Guglielmo Sorci, Roberta Sagheddu, Sara Chiappalupi, Laura Salvadori, Rosario Donato

RAGE in the pathophysiology of skeletal muscle
Emerging evidence suggests that the signalling of the Receptor for Advanced Glycation End products (RAGE) is critical for skeletal muscle physiology controlling both the activity of muscle precursors during skeletal muscle development and the correct time of muscle regeneration after acute injury. On the other hand, the aberrant re‐expression/activity of RAGE in adult skeletal muscle is a hallmark of muscle wasting that occurs in response to ageing, genetic disorders, inflammatory conditions, cancer, and metabolic alterations. In this review, we discuss the mechanisms of action and the ligands of RAGE involved in myoblast differentiation, muscle regeneration, and muscle pathological conditions. We highlight potential therapeutic strategies for targeting RAGE to improve skeletal muscle function.

Riuzzi, F., Sorci, G., Sagheddu, R., Chiappalupi, S., Salvadori, L., and Donato, R. (2018) RAGE in the pathophysiology of skeletal muscle. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12350.

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     Article first published online:  4 October 2018

Maria Conte, Andrea Armani, Giuseppe Conte, Andrea Serra, Claudio Franceschi, Marcello Mele, Marco Sandri, Stefano Salvioli

Muscle-specific Perilipin2 down-regulation affects lipid metabolism and induces myofiber hypertrophy
Background
Perilipin2 (Plin2) belongs to a family of five highly conserved proteins, known for their role in lipid storage. Recent data indicate that Plin2 has an important function in cell metabolism and is involved in several human pathologies, including liver steatosis and Type II diabetes. An association between Plin2 and lower muscle mass and strength has been found in elderly and inactive people, but its function in skeletal muscle is still unclear. Here, we addressed the role of Plin2 in adult muscle by gain and loss of function experiments.
Methods
By mean of in vivo Plin2 down-regulation (shPlin2) and overexpression (overPlin2) in murine tibialis anterior muscle, we analysed the effects of Plin2 genetic manipulations on myofiber size and lipid composition. An analysis of skeletal muscle lipid composition was also performed in vastus lateralis samples from young and old patients undergoing hip surgery.
Results
We found that Plin2 down-regulation was sufficient to induce a 30% increase of myofiber cross-sectional area, independently of mTOR pathway. Alterations of lipid content and modulation of genes involved in lipid synthesis occurred in hypertrophic muscles. In particular, we showed a decrease of triglycerides, ceramides, and phosphatidylcoline:phosphatidylethanolamine ratio, a condition known to impact negatively on muscle function. Plin2 overexpression did not change fibre size; however, lipid composition was strongly affected in a way that is similar to that observed in human samples from old patients.
Conclusions
Altogether these data indicate that Plin2 is a critical mediator for the control of muscle mass, likely, but maybe not exclusively, through its critical role in the regulation of intracellular lipid content and composition.

Conte, M., Armani, A., Conte, G., Serra, A., Franceschi, C., Mele, M., Sandri, M., and Salvioli, S. (2018) Muscle-specific Perilipin2 down-regulation affects lipid metabolism and induces myofiber hypertrophy. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12355.

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