Article first published online: 18 May 20
Marta Gonzalez‐Freire, Fatemeh Adelnia, Ruin Moaddel, Luigi Ferrucci
Searching for a mitochondrial root to the decline in muscle function with ageingSarcopenia, the age‐related loss of muscle mass and strength, is linked to a range of adverse outcomes, such as impaired physical performance, cognitive function, and mortality. Preventing sarcopenia may reduce the burden of functional decline with aging and its impact on physiological and economic well‐being in older adults. Mitochondria in muscle cells lose their intrinsic efficiency and capacity to produce energy during aging, and it has been hypothesized that such a decline is the main driver of sarcopenia. Oxidative phosphorylation becomes impaired with aging, affecting muscle performance, and contributing to an age‐associated decline in mobility. However, it is unclear whether this deterioration is due to a reduced mitochondria population, decreased mitochondrial energetic efficiency, or a reduced capacity to dynamically transport oxygen and nutrients into the mitochondria, and addressing these questions is an active area of research. Further research in humans will require use of new “omics” technologies, progress in neuroimaging techniques that permit energy production assessment, and visualization of molecules critical for energetic metabolism, as well as proxy biomarkers of muscle perfusion.
Gonzalez‐Freire, M., Adelnia, F., Moaddel, R., and Ferrucci, L. (2018) Searching for a mitochondrial root to the decline in muscle function with ageing. Journal of Cachexia, Sarcopenia and Muscle, 9: 435–440. doi: 10.1002/jcsm.12313.
Article first published online: 05 June 2018
Nicole Ebner, Maciej Banach, Stefan D. Anker, Stephan von Haehling
Ebner, N., Banach, M., Anker, S. D., and von Haehling, S. (2018) From meta‐analysis to Cochrane reviews. Journal of Cachexia, Sarcopenia and Muscle, 9: 441–443. doi: 10.1002/jcsm.12312.
Article first published online: 14 MAR 2018
Vicente Ruiz-García, Eduardo López-Briz, Rafael Carbonell-Sanchis, Sylvia Bort-Martí, José Luis Gonzálvez-Perales
Megestrol acetate for cachexia–anorexia syndrome. A systematic reviewIn 1993, megestrol acetate (MA) was approved by the US Food and Drug Administration for the treatment of anorexia, cachexia, or unexplained weight loss in patients with acquired immunodeficiency syndrome. The mechanism by which MA increases appetite is unknown, and its effectiveness for anorexia and cachexia in neoplastic, elderly, and acquired immunodeficiency syndrome patients is under investigation. This is an updated version of a Cochrane systematic review first published in 2005 and later updated in 2013 entitled ‘Megestrol acetate for the treatment of anorexia–cachexia syndrome’. MA vs. placebo: in studies where MA was compared with placebo, the overall results showed that MA patients gained weight (mean difference, MD 2.25 kg, 95% CI [1.19, 3.3]) but did not gain quality of life (QOL) (standarized mean difference, SMD 0.5, 95% CI [-0.13, 1.13]), with more adverse events (relative risk, RR 1.46, 95% CI [1.05, 2.04]), but no difference in deaths (RR 1.26, 95% CI [0.70, 2.27]). MA vs. no treatment: MA patients gained weight (MD 1.45 kg, 95% CI [0.15, 2.75]) but did not gain QOL (standardized mean difference 3.89 95% CI [-14, 6.28]). There was no increase in adverse events (RR 0.90, 95% CI [0.39, 2.08]) or deaths (RR 1.01, 95% CI [0.42, 2.45]). MA vs. active drugs: MA patients gained weight (MD 2.5 kg, 95% CI [0.37, 4.64]) but did not gain QOL (MD 0.20 95% CI [-0.02, 0.43]) and did not report an increase in adverse events (RR 1.05 95% CI [0.95, 1.16]) or in deaths (RR 1.53, 95% CI [1.02, 2.29]) Different doses of MA: in studies where lower doses of MA were compared with higher doses of MA, we did not find differences either in weight gain (MD -0.94 kg, 95% CI [-3.33, 1.45]), QOL (MD 0.31 95% CI [-0.19, 0.81]), or adverse events (RR 1.34, 95% CI [0.65, 2.76]). Thus, we cannot reach a conclusion for an optimal dose of MA.
Ruiz‐García, V., López‐Briz, E., Carbonell‐Sanchis, R., Bort‐Martí, S., and Gonzálvez‐Perales, J. L. (2018) Megestrol acetate for cachexia–anorexia syndrome. A systematic review. Journal of Cachexia, Sarcopenia and Muscle, 9: 444–452. doi: 10.1002/jcsm.12292.
Article first published online: 2 FEB 2018
Olaf Verschuren, Ana R.P. Smorenburg, Yvette Luiking, Kristie Bell, Lee Barber, Mark D. Peterson
Determinants of muscle preservation in individuals with cerebral palsy across the lifespan: a narrative review of the literatureIn individuals with cerebral palsy (CP), smaller muscle and atrophy are present at young age. Many people with CP also experience a decline in gross motor function as they age, which might be explained by the loss of muscle mass. The clinical observation of muscle wasting has prompted a comparison with sarcopenia in older adults, and the term accelerated musculoskeletal ageing is often used to describe the hallmark phenotype of CP through the lifespan. However, there has been very little research emphasis on the natural history of ageing with CP and even less with respect to the determinants or prevention of muscle loss with CP.
Considering the burgeoning interest in the science of muscle preservation, this paper aims to (i) describe the characteristics of accelerated musculoskeletal ageing in people with CP, (ii) describe the pathophysiology of sarcopenia and parallels with CP, and (iii) discuss possible therapeutic approaches, based on established approaches for sarcopenia.
Verschuren, O., Smorenburg, A. R. P., Luiking, Y., Bell, K., Barber, L., and Peterson, M. D. (2018) Determinants of muscle preservation in individuals with cerebral palsy across the lifespan: a narrative review of the literature. Journal of Cachexia, Sarcopenia and Muscle, 9: 453-464. doi: 10.1002/jcsm.12287.
Article first published online: 15 MAR 2018
Jared W. Skinner Dana M. Otzel Andrew Bowser Daniel Nargi Sanjay Agarwal Mark D. Peterson Baiming Zou Stephen E. Borst Joshua F. Yarrow
Muscular responses to testosterone replacement vary by administration route: a systematic review and meta-analysisBackground
Inconsistent fat-free mass (FFM) and muscle strength responses have been reported in randomized clinical trials (RCTs) administering testosterone replacement therapy (TRT) to middle-aged and older men. Our objective was to conduct a meta-analysis to determine whether TRT improves FFM and muscle strength in middle-aged and older men and whether the muscular responses vary by TRT administration route.
Systematic literature searches of MEDLINE/PubMed and the Cochrane Library were conducted from inception through 31 March 2017 to identify double-blind RCTs that compared intramuscular or transdermal TRT vs. placebo and that reported assessments of FFM or upper-extremity or lower-extremity strength. Studies were identified, and data were extracted and validated by three investigators, with disagreement resolved by consensus. Using a random effects model, individual effect sizes (ESs) were determined from 31 RCTs reporting FFM (sample size: n = 1213 TRT, n = 1168 placebo) and 17 reporting upper-extremity or lower-extremity strength (n = 2572 TRT, n = 2523 placebo). Heterogeneity was examined, and sensitivity analyses were performed.
When administration routes were collectively assessed, TRT was associated with increases in FFM [ES = 1.20 ± 0.15 (95% CI: 0.91, 1.49)], total body strength [ES = 0.90 ± 0.12 (0.67, 1.14)], lower-extremity strength [ES = 0.77 ± 0.16 (0.45, 1.08)], and upper-extremity strength [ES = 1.13 ± 0.18 (0.78, 1.47)] (P < 0.001 for all). When administration routes were evaluated separately, the ES magnitudes were larger and the per cent changes were 3–5 times greater for intramuscular TRT than for transdermal formulations vs. respective placebos, for all outcomes evaluated. Specifically, intramuscular TRT was associated with a 5.7% increase in FFM [ES = 1.49 ± 0.18 (1.13, 1.84)] and 10–13% increases in total body strength [ES = 1.39 ± 0.12 (1.15, 1.63)], lower-extremity strength [ES = 1.39 ± 0.17 (1.07, 1.72)], and upper-extremity strength [ES = 1.37 ± 0.17 (1.03, 1.70)] (P < 0.001 for all). In comparison, transdermal TRT was associated with only a 1.7% increase in FFM [ES = 0.98 ± 0.21 (0.58, 1.39)] and only 2–5% increases in total body [ES = 0.55 ± 0.17 (0.22, 0.88)] and upper-extremity strength [ES = 0.97 ± 0.24 (0.50, 1.45)] (P < 0.001). Interestingly, transdermal TRT produced no change in lower-extremity strength vs. placebo [ES = 0.26 ± 0.23 (-0.19, 0.70), P = 0.26]. Subanalyses of RCTs limiting enrolment to men =60 years of age produced similar results.
Intramuscular TRT is more effective than transdermal formulations at increasing LBM and improving muscle strength in middle-aged and older men, particularly in the lower extremities.
Skinner, J. W., Otzel, D. M., Bowser, A., Nargi, D., Agarwal, S., Peterson, M. D., Zou, B., Borst, S. E., and Yarrow, J. F. (2018) Muscular responses to testosterone replacement vary by administration route: a systematic review and meta-analysis. Journal of Cachexia, Sarcopenia and Muscle, 9: 465-481. doi: 10.1002/jcsm.12291.
Article first published online: 14 APR 2018
A randomized trial of adjunct testosterone for cancer-related muscle loss in men and women Background
Cancer cachexia negatively impacts cancer-related treatment options, quality of life, morbidity, and mortality, yet no established therapies exist. We investigated the anabolic properties of testosterone to limit the loss of body mass in late stage cancer patients undergoing standard of care cancer treatment.
A randomized, double-blind, placebo-controlled phase II clinical trial was undertaken to assess the potential therapeutic role of adjunct testosterone to limit loss of body mass in patients with squamous cell carcinoma of the cervix or head and neck undergoing standard of care treatment including chemotherapy and chemoradiation. Patients were randomly assigned in blocks to receive weekly injections of either 100 mg testosterone enanthate or placebo for 7 weeks. The primary outcome was per cent change in lean body mass, and secondary outcomes included assessment of quality of life, tests of physical performance, muscle strength, daily activity levels, resting energy expenditure, nutritional intake, and overall survival.
A total of 28 patients were enrolled, 22 patients were studied to completion, and 21 patients were included in the final analysis (12 placebo, nine testosterone). Adjunct testosterone increased lean body mass by 3.2% (95% confidence interval [CI], 0–7%) whereas those receiving placebo lost 3.3% (95% CI, -7% to 1%, P = 0.015). Although testosterone patients maintained more favourable body condition, sustained daily activity levels, and showed meaningful improvements in quality of life and physical performance, overall survival was similar in both treatment groups.
In patients with advanced cancer undergoing the early phase of standard of care therapy, adjunct testosterone improved lean body mass and was also associated with increased quality of life, and physical activity compared with placebo.
Wright, T. J., Dillon, E. L., Durham, W. J., Chamberlain, A., Randolph, K. M., Danesi, C., Horstman, A. M., Gilkison, C. R., Willis, M., Richardson, G., Hatch, S. S., Jupiter, D. C., McCammon, S., Urban, R. J., and Sheffield-Moore, M. (2018) A randomized trial of adjunct testosterone for cancer-related muscle loss in men and women. Journal of Cachexia, Sarcopenia and Muscle, 9: 482-496. doi: 10.1002/jcsm.12295.
Article first published online: 25 MAR 2018
Maria Maldonado, David L. Molfese, Humsini Viswanath ,Kaylah Curtis, Ashley Jones, Teresa G. Hayes, Marco Marcelli, Sanjay Mediwala, Philip Baldwin, Jose M. Garcia, Ramiro Salas
The habenula as a novel link between the homeostatic and hedonic pathways in cancer-associated weight loss: a pilot studyBackground
Little is known about the brain mechanisms underlying cancer-associated weight loss (C-WL) in humans despite this condition negatively affecting their quality of life and survival. We tested the hypothesis that patients with C-WL have abnormal connectivity in homeostatic and hedonic brain pathways together with altered brain activity during food reward.
In 12 patients with cancer and 12 healthy controls, resting-state functional connectivity (RSFC, resting brain activity observed through changes in blood flow in the brain which creates a blood oxygen level-dependent signal that can be measured using functional magnetic resonance imaging) was used to compare three brain regions hypothesized to play a role in C-WL: the hypothalamus (homeostatic), the nucleus accumbens (hedonic), and the habenula (an important regulator of reward). In addition, the brain reward response to juice was studied.
Participants included 12 patients with histological diagnosis of incurable cancer (solid tumours), a European Cooperative Oncology Group performance status of 0–2, and a =5% involuntary body weight loss from pre-illness over the previous 6 months and 12 non-cancer controls matched for age, sex, and race. RSFC between the hypothalamus, nucleus accumbens, and habenula and brain striatum activity as measured by functional MRI during juice reward delivery events were the main outcome measures.
After adjusting for BMI and compared with matched controls, patients with C-WL were found to have reduced RSFC between the habenula and hypothalamus (P = 0.04) and between the habenula and nucleus accumbens (P = 0.014). Patients with C-WL also had reduced juice reward responses in the striatum compared with controls.
In patients with C-WL, reduced connectivity between both homeostatic and hedonic brain regions and the habenula and reduced juice reward were observed. Further research is needed to establish the relevance of the habenula and striatum in C-WL.
Maldonado, M., Molfese, D. L., Viswanath, H., Curtis, K., Jones, A., Hayes, T. G., Marcelli, M., Mediwala, S., Baldwin, P., Garcia, J. M., and Salas, R. (2018) The habenula as a novel link between the homeostatic and hedonic pathways in cancer-associated weight loss: a pilot study. Journal of Cachexia, Sarcopenia and Muscle, 9: 497-504. doi: 10.1002/jcsm.12286.
Article first published online: 25 FEB 2018
Roman Mayr, Michael Gierth, Florian Zeman, Marieke Reiffen, Philipp Seeger, Felix Wezel, Armin Pycha, Evi Comploj, Matteo Bonatti, Manuel Ritter, Bas W.G. van Rhijn, Maximilian Burger, Christian Bolenz, Hans-Martin Fritsche, Thomas Martini
Sarcopenia as a comorbidity-independent predictor of survival following radical cystectomy for bladder cancerObjective
A multicentre study was conducted to investigate the impact of sarcopenia as an independent predictor of oncological outcome after radical cystectomy for bladder cancer.
In total, 500 patients with available digital computed tomography scans of the abdomen obtained within 90 days before surgery were identified. The lumbar skeletal muscle index was measured using pre-operative computed tomography. Cancer-specific survival (CSS) and overall survival (OS) were estimated using Kaplan–Meier curves. Predictors of CSS and OS were analysed by univariable and multivariable Cox regression models.
Based on skeletal muscle index, 189 patients (37.8%) were classified as sarcopenic. Patients with sarcopenia were older compared with their counterparts (P = 0.002), but both groups were comparable regarding to gender, comorbidity, tumor, node, metastasis (TNM) stage, and type of urinary diversion (all P > 0.05). In total, 234 (46.8%) patients died, and of these, 145 (29.0%) died because of urothelial carcinoma of the bladder. Sarcopenic patients had significantly worse 5 year OS (38.3% vs. 50.5%; P = 0.002) and 5 year CSS (49.5% vs. 62.3%; P = 0.016) rates compared with patients without sarcopenia. Moreover, sarcopenia was associated independently with both increased all-cause mortality (hazard ratio, 1.43; 95% confidence interval 1.09–1.87; P = 0.01) and increased cancer-specific mortality (hazard ratio, 1.42; 95% confidence interval, 1.00–2.02; P = 0.048). Our results are limited by the lack of prospective frailty assessment.
Sarcopenia has been shown to be an independent predictor for OS and CSS in a large multicentre study with patients undergoing radical cystectomy for bladder cancer.
Mayr, R., Gierth, M., Zeman, F., Reiffen, M., Seeger, P., Wezel, F., Pycha, A., Comploj, E., Bonatti, M., Ritter, M., van Rhijn, B. W. G., Burger, M., Bolenz, C., Fritsche, H.-M., and Martini, T. (2018) Sarcopenia as a comorbidity-independent predictor of survival following radical cystectomy for bladder cancer. Journal of Cachexia, Sarcopenia and Muscle, 9: 505-513. doi: 10.1002/jcsm.12279.
Article first published online: 02 May 2018
Tuuli A. Nissinen Jaakko Hentilä Fabio Penna Anita Lampinen Juulia H. Lautaoja Vasco Fachada Tanja Holopainen Olli Ritvos Riikka Kivelä Juha J. Hulmi
Treating cachexia using soluble ACVR2B improves survival, alters mTOR localization, and attenuates liver and spleen responsesBackground
Cancer cachexia increases morbidity and mortality, and blocking of activin receptor ligands has improved survival in experimental cancer. However, the underlying mechanisms have not yet been fully uncovered.
The effects of blocking activin receptor type 2 (ACVR2) ligands on both muscle and non‐muscle tissues were investigated in a preclinical model of cancer cachexia using a recombinant soluble ACVR2B (sACVR2B‐Fc). Treatment with sACVR2B‐Fc was applied either only before the tumour formation or with continued treatment both before and after tumour formation. The potential roles of muscle and non‐muscle tissues in cancer cachexia were investigated in order to understand the possible mechanisms of improved survival mediated by ACVR2 ligand blocking.
Blocking of ACVR2 ligands improved survival in tumour‐bearing mice only when the mice were treated both before and after the tumour formation. This occurred without effects on tumour growth, production of pro‐inflammatory cytokines or the level of physical activity. ACVR2 ligand blocking was associated with increased muscle (limb and diaphragm) mass and attenuation of both hepatic protein synthesis and splenomegaly. Especially, the effects on the liver and the spleen were observed independent of the treatment protocol. The prevention of splenomegaly by sACVR2B‐Fc was not explained by decreased markers of myeloid‐derived suppressor cells. Decreased tibialis anterior, diaphragm, and heart protein synthesis were observed in cachectic mice. This was associated with decreased mechanistic target of rapamycin (mTOR) colocalization with late‐endosomes/lysosomes, which correlated with cachexia and reduced muscle protein synthesis.
The prolonged survival with continued ACVR2 ligand blocking could potentially be attributed in part to the maintenance of limb and respiratory muscle mass, but many observed non‐muscle effects suggest that the effect may be more complex than previously thought. Our novel finding showing decreased mTOR localization in skeletal muscle with lysosomes/late‐endosomes in cancer opens up new research questions and possible treatment options for cachexia.
Nissinen, T. A., Hentilä, J., Penna, F., Lampinen, A., Lautaoja, J. H., Fachada, V., Holopainen, T., Ritvos, O., Kivelä, R., and Hulmi, J. J. (2018) Treating cachexia using soluble ACVR2B improves survival, alters mTOR localization, and attenuates liver and spleen responses. Journal of Cachexia, Sarcopenia and Muscle, 9: 514-529. doi: 10.1002/jcsm.12310.
Article first published online: 22 MAR 2018
Yusuke Osawa, Stephanie A. Studenski, Luigi Ferrucci
Knee extension rate of torque development and peak torque: associations with lower extremity functionBackground
With aging, the ability to generate muscle force decreases, contributing to declines in physical functions such as walking. While most studies assess muscle force by peak torque, the rate of torque development (RTD) reflects a dynamic component of muscle performance that is important for physical function. Using data from the Baltimore Longitudinal Study of Aging, we assessed whether RTD adds significantly to peak torque in associations with lower extremity performance. If so, RTD may help identify weak older adults for screening and intervention.
We assessed associations of RTD and peak torque with physical performance independent of demographics, BMI, body composition, and each other in 1089 Baltimore Longitudinal Study of Aging participants (49.7% women; aged 26 to 96 years; women, 64.0 ± 13.8 years; men, 68.4 ± 14.4 years). Peak torque was assessed by isometric and 30 deg/s isokinetic knee extension tests. Peak RTD was operationalized as the maximum torque-time slope among successive 50 ms epochs over the first 3 s of a test of knee extension isometric strength, with the knee joint positioned at 120 deg of flexion. A battery of lower extremity performance tests included gait speed during a 6 m walk at usual and fast pace (6 m usual and fast), time to complete a 400 m walk at fast pace (400 m), distance covered in a 2.5 min walk at normal pace (2.5 min), time to complete 5 and 10 chair stands, and two summary tests of lower extremity performance. Sex-stratified generalized linear regression models were adjusted for age, race, BMI, appendicular lean mass, and whole body fat mass.
In men, independent of either measure of peak torque and cofactors, RTD was a significant (P < 0.05) predictor of all lower extremity performance tests except the 400 m and 2.5 min walks. In women, independent of peak torque, RTD was only a significant independent correlate of the 6 m fast walk (P < 0.001).
RTD independently contributes to physical functions in men but less in women. The mechanisms underlying the sex difference are unclear and require further study.
Osawa, Y., Studenski, S. A., and Ferrucci, L. (2018) Knee extension rate of torque development and peak torque: associations with lower extremity function. Journal of Cachexia, Sarcopenia and Muscle, 9: 530-539. doi: 10.1002/jcsm.12285.
Article first published online: 16 APR 2018
Mahalakshmi Shankaran, Gregg Czerwieniec, Chancy Fessler, Po-yin Anne Wong, Salena Killion, Scott M. Turner, Marc K. Hellerstein, William J. Evans
Dilution of oral D3-Creatine to measure creatine pool size and estimate skeletal muscle mass: development of a correction algorithm Background
Muscle mass can be measured directly in vivo by isotope dilution, using Creatine‐(methyl‐d3) monohydrate (D3‐Cr) by mouth followed by measurement of the steady‐state enrichment of D3‐creatinine (D3‐Crn) in urine. Isotope dilution methods require knowledge of the amount of tracer delivered to the pool of interest. In a subset of human subjects, a small amount of orally administered D3‐Cr ‘spills’ into urine after absorption and prior to transport into skeletal muscle cells. The objectives were to develop a method to correct for spillage to compare the estimate of muscle mass by D3‐Cr dilution to other assessments of fat‐free mass.
Subjects (19 males, 23–81 years old; 20 females, 20–77 years old) ingested a single dose of 60 mg D3‐Cr and urine was collected prior to and daily for 4 days following the dose. Fasting morning urine samples was assessed for D3‐Cr, total Cr, D3‐Crn, and total Crn concentrations, as well as isotopic enrichments of D3‐Crn, by LC/MS. The 24‐h urine collections over 3 days after the dose of D3‐Cr were also performed to determine D3‐Cr spillage. Total body water, fat mass, and fat‐free mass were assessed by bioelectrical impedance spectroscopy (BIS).
Spillage of D3‐Cr in the urine was greater in women than men. D3‐Crn enrichment and the ratio of Cr/Crn were used in an algorithm to calculate Cr pool size and muscle mass. Specifically, an algorithm was developed for the estimation of spillage based on the relationship between the fasting Cr/Crn ratio and the cumulative proportion of the D3‐Cr dose excreted over 3 days based on 24‐h urine collections. Muscle mass corrected using the algorithm based on fasting urine levels correlated (r = 0.9967, P < 0.0001) with that corrected by measuring D3‐Cr dose excreted. Muscle mass measured by D3‐Crn enrichment also correlated (r = 0.8579, P < 0.0001, algorithm corrected) with that measured by 24‐h Crn excretion. Muscle mass measured by D3‐Cr dilution method correlated with intracellular water by BIS, whether using spillage corrected by the algorithm (r = 0.9041, P < 0.0001) or measured by 3 day D3‐Cr losses (r = 0.91, P < 0.0001) and similarly correlated with fat‐free mass by BIA (r = 0.8857 and 0.8929, P < 0.0001, respectively).
The D3‐Cr dilution method is further validated here as a non‐invasive, easy‐to‐use test for measuring muscle mass. The technical issue of D3‐Cr spillage can be corrected for with a simple algorithm based on fasting spot urine samples. Muscle mass by Cr dilution potentially has broad applications in clinical and research settings.
Shankaran, M., Czerwieniec, G., Fessler, C., Wong, P.-. A., Killion, S., Turner, S. M., Hellerstein, M. K., and Evans, W. J. (2018) Dilution of oral D3-Creatine to measure creatine pool size and estimate skeletal muscle mass: development of a correction algorithm. Journal of Cachexia, Sarcopenia and Muscle, 9: 540-546. doi: 10.1002/jcsm.12278.
Article first published online: 23 MAR 2018
Michal Tkaczyszyn, Marcin Drozd, Kinga Wegrzynowska-Teodorczyk, Irena Flinta, Kamil Kobak, Waldemar Banasiak, Piotr Ponikowski, Ewa A. Jankowska
Depleted iron stores are associated with inspiratory muscle weakness independently of skeletal muscle mass in men with systolic chronic heart failureBackground
Skeletal and respiratory muscle dysfunction constitutes an important pathophysiological feature of heart failure (HF). We assessed the relationships between respiratory muscle function, skeletal muscle mass, and physical fitness in men with HF with reduced left ventricular ejection fraction (HFrEF), and investigated the hypothesis of whether iron deficiency (ID) contributes to respiratory muscle dysfunction in these patients.
We examined 53 male outpatients with stable HFrEF without asthma or chronic obstructive pulmonary disease (age: 64 ± 10 years; New York Heart Association [NYHA] class I/II/III: 36/51/13%; ischaemic aetiology: 83%; all with left ventricular ejection fraction =40%) and 10 middle-aged healthy men (control group). We analysed respiratory muscle function (maximal inspiratory and expiratory pressure at the mouth [MIP and MEP, respectively]), appendicular lean mass/body mass index (ALM/BMI; ALM was measured using dual-energy X-ray absorptiometry), physical fitness (components of Functional Fitness Test for Older Adults), and iron status.
MIP, MEP, and ALM/BMI (but not MIP adjusted for ALM/BMI) were lower in men with HFrEF vs. healthy men. MIP, MEP, and MIP adjusted for ALM/BMI (but not ALM/BMI) were lower in men with HFrEF with vs. without ID. In a multivariable linear regression model lower serum ferritin (but not transferrin saturation) was associated with lower MIP independently of ALM/BMI, left ventricular ejection fraction, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and haemoglobin concentration. In multivariable linear regression models, lower MIP was associated with worse results in Functional Fitness Test when adjusted for ALM/BMI or relevant clinical variables (NYHA class, estimated glomerular filtration rate, NT-proBNP, and haemoglobin concentration).
In men with HFrEF, low ferritin reflecting depleted iron stores is associated with inspiratory muscle weakness independently of skeletal muscle mass. Inspiratory muscle dysfunction correlates with worse physical fitness independently of either skeletal muscle mass or disease severity.
Tkaczyszyn, M., Drozd, M., Wegrzynowska-Teodorczyk, K., Flinta, I., Kobak, K., Banasiak, W., Ponikowski, P., and Jankowska, E. A. (2018) Depleted iron stores are associated with inspiratory muscle weakness independently of skeletal muscle mass in men with systolic chronic heart failure. Journal of Cachexia, Sarcopenia and Muscle, 9: 547-556. doi: 10.1002/jcsm.12282.
Article first published online: 29 JAN 2018
Malgorzata Halon-Golabek, Andzelika Borkowska, Jan J. Kaczor, Wieslaw Ziolkowski, Damian J. Flis, Narcyz Knap, Kajetan Kasperuk, Jedrzej Antosiewicz
hmSOD1 gene mutation-induced disturbance in iron metabolism is mediated by impairment of Akt signalling pathwayBackground
Recently, skeletal muscle atrophy, impairment of iron metabolism, and insulin signalling have been reported in rats suffering from amyotrophic lateral sclerosis (ALS). However, the interrelationship between these changes has not been studied. We hypothesize that an impaired Akt–FOXO3a signalling pathway triggers changes in the iron metabolism in the muscles of transgenic animals.
In the present study, we used transgenic rats bearing the G93A hmSOD1 gene and their non-transgenic littermates. The study was performed on the muscles taken from animals at three different stages of the disease: asymptomatic (ALS I), the onset of the disease (ALS II), and the terminal stage of the disease (ALS III). In order to study the molecular mechanism of changes in iron metabolism, we used SH-SY5Y and C2C12 cell lines stably transfected with pcDNA3.1, SOD1 WT and SOD1 G93A, or FOXO3a TM-ER.
A significant decrease in P-Akt level and changes in iron metabolism were observed even in the group of ALS I animals. This was accompanied by an increase in the active form of FOXO3a, up-regulation of atrogin-1, and catalase. However, significant muscle atrophy was observed in ALS II animals. An increase in ferritin L and H was accompanied by a rise in PCBP1 and APP protein levels. In SH-SY5Y cells stably expressing SOD1 or SOD1 G93A, we observed elevated levels of ferritin L and H and non-haem iron. Interestingly, insulin treatment significantly down-regulated ferritin L and H proteins in the cell. Conversely, cells transfected with small interfering RNA against Akt 1, 2, 3, respectively, showed a significant increase in the ferritin and FOXO3a levels. In order to assess the role of FOXO3a in the ferritin expression, we constructed a line of SH-SY5Y cells that expressed a fusion protein made of FOXO3a fused at the C-terminus with the ligand-binding domain of the oestrogen receptor (TM-ER) being activated by 4-hydroxytamoxifen. Treatment of the cells with 4-hydroxytamoxifen significantly up-regulated ferritin L and H proteins level.
Our data suggest that impairment of insulin signalling and iron metabolism in the skeletal muscle precedes muscle atrophy and is mediated by changes in Akt/FOXO3a signalling pathways.
Halon-Golabek, M., Borkowska, A., Kaczor, J. J., Ziolkowski, W., Flis, D. J., Knap, N., Kasperuk, K., and Antosiewicz, J. (2018) hmSOD1 gene mutation-induced disturbance in iron metabolism is mediated by impairment of Akt signalling pathway. Journal of Cachexia, Sarcopenia and Muscle, 9: 557-569. doi: 10.1002/jcsm.12283.
Article first published online: 29 JAN 2018
Jia-Rong Jheng, Yuan-Siao Chen, Un Iong Ao, Ding-Cheng Chan, Jenq-Wen Huang, Kuang-Yu Hung, Der-Cheng Tarng, Chih-Kang Chiang
The double-edged sword of endoplasmic reticulum stress in uremic sarcopenia through myogenesis perturbationBackgrounds
Sarcopenia is the age-related degeneration characterized with the decline of skeletal muscle mass, strength, and function. The imbalance of protein synthesis and degradation which jeopardizes immune, hormone regulation, and muscle-motor neuron connection is the main cause of sarcopenia. There is limited knowledge regarding molecular mechanism of sarcopenia. As the endoplasmic reticulum is the control centre of the protein syntheses and degradation, we hypothesized that endoplasmic reticulum stress and unfolded protein response (UPR) play an important in the development of sarcopenia. Understanding the sarcopenia molecular mechanisms may benefit the therapeutic diagnosis and treatment in the future.
Mouse myoblast C2C12 cells are exposed to designated time and concentration of indoxyl sulfate (IS), a uremic toxin of chronic kidney disease. The proliferation, differentiation, and the expression of atrogin 1 are examined. The protein and mRNA expression of IS treated-C2C12 cells are inspected to distinguish the role of ER stress and oxidative stress underlying the sarcopenia.
Indoxyl sulfate inhibits myoblast differentiation. We demonstrate that as the number of multi-nuclei myotube decreased, the differentiation markers including myoD, myoG, and myosin heavy chain are also suppressed. Indoxyl sulfate inhibits myoblast proliferation and induces the myotubular atrophy marker atrogin-1 protein expression. Indoxyl sulfate stimulates eIF2a phosphorylation and XBP1 mRNA splicing in UPR. Interestingly, the oxidative stress is related to eIF2a phosphorylation but not XBP1 mRNA splicing. The eIF2a phosphorylation triggered by IS reduces myoD, myoG, and myosin heavy chain protein expression, which represents the anti-myogenic modulation on the early differentiation event. The XBP1 mRNA splicing induced by IS, however, is considered the adaptive response to restore the myogenic differentiation.
Our studies indicated that the ER stress and UPR modulation are critical in the chronic kidney disease uremic toxin-accumulated sarcopenia model. We believe that UPR-related signals showed great potential in clinical application.
Jheng, J.-R., Chen, Y.-S., Ao, U. I., Chan, D.-C., Huang, J.-W., Hung, K.-Y., Tarng, D.-C., and Chiang, C.-K. (2018) The double-edged sword of endoplasmic reticulum stress in uremic sarcopenia through myogenesis perturbation. Journal of Cachexia, Sarcopenia and Muscle, 9: 570-584. doi: 10.1002/jcsm.12288.
Article first published online: 6 MAR 2018
Hsien-Chun Chiu, Chen-Yuan Chiu, Rong-Sen Yang, Ding-Cheng Chan, Shing-Hwa Liu, Chih-Kang Chiang
Preventing muscle wasting by osteoporosis drug alendronate in vitro and in myopathy models via sirtuin-3 down-regulationBackground
A global consensus on the loss of skeletal muscle mass and function in humans refers as sarcopenia and cachexia including diabetes, obesity, renal failure, and osteoporosis. Despite a current improvement of sarcopenia or cachexia with exercise training and supportive therapies, alternative and specific managements are needed to discover for whom are unable or unwilling to embark on these treatments. Alendronate is a widely used drug for osteoporosis in the elderly and postmenopausal women. Osteopenic menopausal women with 6 months of alendronate therapy have been observed to improve not only lumbar bone mineral density but also handgrip strength. However, the effect and mechanism of alendronate on muscle strength still remain unclear. Here, we investigated the therapeutic potential and the molecular mechanism of alendronate on the loss of muscle mass and strength in vitro and in vivo.
Mouse myoblasts and primary human skeletal muscle-derived progenitor cells were used to assess the effects of low-dose alendronate (0.1–1 µM) combined with or without dexamethasone on myotube hypertrophy and myogenic differentiation. Moreover, we also evaluated the effects of low-dose alendronate (0.5 and 1 mg/kg) by oral administration on the limb muscle function and morphology of mice with denervation-induced muscle atrophy and glycerol-induced muscle injury.
Alendronate inhibited dexamethasone-induced myotube atrophy and myogenic differentiation inhibition in mouse myoblasts and primary human skeletal muscle-derived progenitor cells. Alendronate significantly abrogated dexamethasone-up-regulated sirtuin-3 (SIRT3), but not SIRT1, protein expression in myotubes. Both SIRT3 inhibitor AKG7 and SIRT3-siRNA transfection could also reverse dexamethasone-up-regulated atrogin-1 and SIRT3 protein expressions. Animal studies showed that low-dose alendronate by oral administration ameliorated the muscular malfunction in mouse models of denervation-induced muscle atrophy and glycerol-induced muscle injury with a negative regulation of SIRT3 expression.
The putative mechanism by which muscle atrophy was improved with alendronate might be through the SIRT3 down-regulation. These findings suggest that alendronate can be a promising therapeutic strategy for management of muscle wasting-related diseases and sarcopenia.
Chiu, H.-C., Chiu, C.-Y., Yang, R.-S., Chan, D.-C., Liu, S.-H., and Chiang, C.-K. (2018) Preventing muscle wasting by osteoporosis drug alendronate in vitro and in myopathy models via sirtuin-3 down-regulation. Journal of Cachexia, Sarcopenia and Muscle, 9: 585-602. doi: 10.1002/jcsm.12289.
Article first published online: 25 MAR 2018
Paulo V.G. Alabarse, Priscila S. Lora, Jordana M.S. Silva, Rafaela C.E. Santo, Eduarda C. Freitas, Mayara S. de Oliveira, Andrelise S. Almeida, Mônica Immig, Vivian O.N. Teixeira, Lidiane I. Filippin, Ricardo M. Xavier
Collagen-induced arthritis as an animal model of rheumatoid cachexiaBackground
Rheumatoid arthritis is characterized by chronic polyarticular synovitis and presents systemic changes that impact quality of life, such as impaired muscle function, seen in up to 66% of the patients. This can progress to severely debilitating state known as rheumatoid cachexia—without loss of fat mass and body weight—for which there is little consensus in terms of diagnosis or treatment. This study aims to evaluate whether the collagen-induced arthritis (CIA) animal model also develops clinical and functional features characteristic of rheumatoid cachexia.
Male DBA1/J mice were randomly divided into 2 groups: healthy animals (CO, n = 11) and CIA animals (n = 13). The clinical score and edema size, animal weight and food intake, free exploratory locomotion, grip strength, and endurance exercise performance were tested 0, 18, 35, 45, 55, and 65 days after disease induction. After euthanasia, several organs, visceral and brown fat, and muscles were dissected and weighed. Muscles were used to assess myofiber diameter. Ankle joint was used to assess arthritis severity by histological score. Statistical analysis were performed using one-way and two-way analyses of variance followed by Tukey's and Bonferroni's test or t-test of Pearson and statistical difference were assumed for a P value under 0.05.
The CIA had significantly higher arthritis scores and larger hind paw edema volumes than CO. The CIA had decreased endurance exercise performance total time (fatigue; 23, 22, 24, and 21% at 35, 45, 55, and 65 days, respectively), grip strength (27, 55, 63, 60, and 66% at 25, 35, 45, 55, and 65 days, respectively), free locomotion (43, 57, 59, and 66% at 35, 45, 55, and 65 days, respectively), and tibialis anterior and gastrocnemius muscle weight (25 and 24%, respectively) compared with CO. Sarcoplasmic ratios were also reduced in CIA (TA: 23 and GA: 22% less sarcoplasmic ratio), confirming the atrophy of skeletal muscle mass in these animals than in CO. Myofiber diameter was also reduced 45% in TA and 41% in GA in CIA when compared with the CO. Visceral and brown fat were lighter in CIA (54 and 39%, respectively) than CO group.
The CIA model is a valid experimental model for rheumatoid cachexia given that the clinical changes observed were similar to those described in patients with rheumatoid arthritis.
Alabarse, P. V. G., Lora, P. S., Silva, J. M. S., Santo, R. C. E., Freitas, E. C., de Oliveira, M. S., Almeida, A. S., Immig, M., Teixeira, V. O. N., Filippin, L. I., and Xavier, R. M. (2018) Collagen-induced arthritis as an animal model of rheumatoid cachexia. Journal of Cachexia, Sarcopenia and Muscle, 9: 603-612. doi: 10.1002/jcsm.12280.
Article first published online: 7 MAR 2018
Zong-Kang Zhang, Jie Li, Daogang Guan, Chao Liang, Zhenjian Zhuo, Jin Liu, Aiping Lu, Ge Zhang, Bao-Ting Zhang
A newly identified lncRNA MAR1 acts as a miR-487b sponge to promote skeletal muscle differentiation and regenerationBackground
Skeletal muscle atrophy induced by either aging (sarcopenia) or mechanical unloading is associated with serious health consequences. Long non-coding RNAs (lncRNAs) are implicated as important regulators in numerous physiological and pathological processes.
Microarray analysis was performed to identify the differentially expressed lncRNAs in skeletal muscle between adult and aged mice. The most decreased lncRNA in aged skeletal muscle was identified. The C2C12 mouse myoblast cells were used to assess the biological function of the lncRNA in vitro. The target microRNA of lncRNA and the target protein of microRNA were predicted by bioinformatics analysis and validated in vitro. Furthermore, the biology function of the lncRNA in vivo was investigated by local overexpression or knockdown the lncRNA in skeletal muscle. The therapeutic effect of the lncRNA overexpression in age-related or mechanical unloading-induced muscle atrophy was also evaluated.
We identified a novel lncRNA (muscle anabolic regulator 1, MAR1) which was highly expressed in mice skeletal muscle and positively correlated with muscle differentiation and growth in vitro and in vivo. We predicted and validated that microRNA-487b (miR-487b) was a direct target of MAR1. We also predicted and validated that Wnt5a, an important regulator during myogenesis, was a target of miR-487b in C2C12 cells. Our findings further demonstrated that enforced MAR1 expression in myoblasts led to derepression of Wnt5a. Moreover, MAR1 promoted skeletal muscle mass/strength and Wnt5a protein level in mice. Enforced MAR1 expression in mice attenuated muscle atrophy induced by either aging or unloading.
The newly identified lncRNA MAR1 acts as a miR-487b sponge to regulate Wnt5a protein, resulting in promoting muscle differentiation and regeneration. MAR1 could be a novel therapeutic target for treating muscle atrophy induced by either aging or mechanical unloading.
Zhang, Z.-K., Li, J., Guan, D., Liang, C., Zhuo, Z., Liu, J., Lu, A., Zhang, G., and Zhang, B.-T. (2018) A newly identified lncRNA MAR1 acts as a miR-487b sponge to promote skeletal muscle differentiation and regeneration. Journal of Cachexia, Sarcopenia and Muscle, 9: 613-626. doi: 10.1002/jcsm.12281.
Article first published online: 23 MAR 2018
Willemke Nijholt, Harriët Jager-Wittenaar, Aldo Scafoglieri, Johannes S.M. Hobbelen, Cees van der Schans
Nijholt, W., Jager-Wittenaar, H., Scafoglieri, A., Hobbelen, J. S. M., and van der Schans, C. (2018) Response to: “The use of ultrasound for the estimation of muscle mass: one site fits most?”. Journal of Cachexia, Sarcopenia and Muscle, 9: 627-628. doi: 10.1002/jcsm.12293.