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To examine the independent associations of leisure-time aerobic physical activity (PA) and resistance exercise (RE) on all-cause mortality in cancer survivors. Patients included 2863 male and female cancer survivors, aged 18 to 81 years, who received a preventive medical examination between April 8, 1987, and December 27, 2002, while enrolled in the Aerobics Center Longitudinal Study in Dallas, Texas. Physical activity and RE were assessed by self-report at the baseline medical examination. Cox proportional hazards regression analysis was performed to determine the independent associations of PA and RE with all-cause mortality in participants who had a history of cancer. Physical activity in cancer survivors was not associated with a lower risk of all-cause mortality. In contrast, RE was associated with a 33% lower risk of all-cause mortality (95% CI, 0.45-0.99) after adjusting for potential confounders, including PA. Individuals who participated in RE during cancer survival had a lower risk for all-cause mortality. The present findings provide preliminary evidence for benefits of RE during cancer survival. Future randomized controlled trials examining RE and its effect on lean body mass, muscular strength, and all-cause mortality in cancer survivors are warranted.

Background Oxidative stress is implicated in the insidious loss of muscle mass and strength that occurs with age. However, few studies have investigated the role of iron, which is elevated during ageing, in age‐related muscle wasting and blunted repair after injury. We hypothesized that iron accumulation leads to membrane lipid peroxidation, muscle wasting, increased susceptibility to injury, and impaired muscle regeneration. Methods To examine the role of iron in age‐related muscle atrophy, we compared the skeletal muscles of 3‐month‐old with 22‐ to 24‐month‐old 129SvEv FVBM mice. We assessed iron distribution and total elemental iron using laser ablation inductively coupled plasma mass spectrometry and Perls' stain on skeletal muscle cross‐sections. In addition, old mice underwent ischaemia–reperfusion (IR) injury (90 min ischaemia), and muscle regeneration was assessed 14 days after injury. Immunoblotting was used to determine lipid peroxidation (4HNE) and iron‐related proteins. To determine whether muscle iron content can be altered, old mice were treated with deferiprone (DFP) in the drinking water, and we assessed its effects on muscle regeneration after injury. Results We observed a significant increase in total elemental iron (+43%, P < 0.05) and lipid peroxidation (4HNE: +76%, P < 0.05) in tibialis anterior muscles of old mice. Iron was further increased after injury (adult: +81%, old: +135%, P < 0.05) and associated with increased lipid peroxidation (+41%, P < 0.05). Administration of DFP did not impact iron or measures of lipid peroxidation in skeletal muscle or modulate muscle mass. Increased muscle iron concentration and lipid peroxidation were associated with less efficient regeneration, evident from the smaller fibres in cross‐sections of tibialis anterior muscles (−24%, P < 0.05) and an increased percentage of fibres with centralized nuclei (+4124%, P < 0.05) in muscles of old compared with adult mice. Administration of DFP lowered iron after IR injury (PRE: −32%, P < 0.05 and POST: −41%, P < 0.05), but did not translate to structural improvements. Conclusions Muscles from old mice have increased iron levels, which are associated with increased lipid peroxidation, increased susceptibility to IR injury, and impaired muscle regeneration. Our results suggest that iron is involved in effective muscle regeneration, highlighting the importance of iron homeostasis in muscle atrophy and muscle repair.

Cancer cachexia, a wasting syndrome characterized by skeletal muscle depletion, contributes to increased patient morbidity and mortality. While the intricate balance between protein synthesis and breakdown regulates skeletal muscle mass, the suppression of basal protein synthesis may not account for the severe wasting induced by cancer. Therefore, recent research has shifted to the regulation of “anabolic resistance,” which is the impaired ability of nutrition and exercise to stimulate protein synthesis. Emerging evidence suggests that oxidative metabolism can regulate both basal and induced muscle protein synthesis. While disrupted protein turnover and oxidative metabolism in cachectic muscle have been examined independently, evidence suggests a linkage between these processes for the regulation of cancer-induced wasting. The primary objective of this review is to highlight the connection between dysfunctional oxidative metabolism and cancer-induced anabolic resistance in skeletal muscle. First, we review oxidative metabolism regulation of muscle protein synthesis. Second, we describe cancer-induced alterations in the response to an anabolic stimulus. Finally, we review a role for exercise to inhibit cancer-induced anabolic suppression and mitochondrial dysfunction.

Background Oxidative stress is implicated in the pathophysiology of Duchenne muscular dystrophy (DMD, caused by mutations in the dystrophin gene), which is the most common and severe of the muscular dystrophies. To our knowledge, the distribution of iron, an important modulator of oxidative stress, has not been assessed in DMD. We tested the hypotheses that iron accumulation occurs in mouse models of DMD and that modulation of iron through the diet or chelation could modify disease severity. Methods We assessed iron distribution and total elemental iron using LA‐ICP‐MS on skeletal muscle cross‐sections of 8‐week‐old Bl10 control mice and dystrophic mdx mice (with moderate dystrophy) and dystrophin/utrophin‐null mice (dko, with severe dystrophy). In addition, mdx mice (4 weeks) were treated with either an iron chelator (deferiprone 150 mg/kg/day) or iron‐enriched feed (containing 1% added iron as carbonyl iron). Immunoblotting was used to determine the abundance of iron‐ and mitochondria‐related proteins. (Immuno)histochemical and mRNA assessments of fibrosis and inflammation were also performed. Results We observed a significant increase in total elemental iron in hindlimb muscles of dko mice (+50%, P < 0.05) and in the diaphragm of mdx mice (+80%, P < 0.05), with both tissues exhibiting severe pathology. Iron dyshomeostasis was further evidenced by an increase in the storage protein ferritin (dko: +39%, P < 0.05) and ferroportin compared with Bl10 control mice (mdx: +152% and dko: +175%, P < 0.05). Despite having features of iron overload, dystrophic muscles had lower protein expression of ALAS‐1, the rate‐limiting enzyme for haem synthesis (dko −44%, P < 0.05), and the haem‐containing protein myoglobin (dko −54%, P < 0.05). Deferiprone treatment tended to decrease muscle iron levels in mdx mice (−30%, P < 0.1), which was associated with lower oxidative stress and fibrosis, but suppressed haem‐containing proteins and mitochondrial content. Increasing iron via dietary intervention elevated total muscle iron (+25%, P < 0.05) but did not aggravate the pathology. Conclusions Muscles from dystrophic mice have increased iron levels and dysregulated iron‐related proteins that are associated with dystrophic pathology. Muscle iron levels were manipulated by iron chelation and iron enriched feed. Iron chelation reduced fibrosis and reactive oxygen species (ROS) but also suppressed haem‐containing proteins and mitochondrial activity. Conversely, iron supplementation increased ferritin and haem‐containing proteins but did not alter ROS, fibrosis, or mitochondrial activity. Further studies are required to investigate the contribution of impaired ferritin breakdown in the dysregulation of iron homeostasis in DMD.

Background Skeletal muscle responds to eccentric contractions (ECC) with an anabolic response that involves the induction of protein synthesis through the mechanistic target of rapamycin complex 1. While we have reported that repeated ECC bouts after cachexia initiation attenuated muscle mass loss and inflammatory signalling, cachectic muscle's capacity to induce protein synthesis in response to ECC has not been determined. Therefore, we examined cachectic muscle's ability to induce mechano‐sensitive pathways and protein synthesis in response to an anabolic stimulus involving ECC and determined the role of muscle signal transducer and activator of transcription 3 (STAT3)/nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NFκB) signalling on ECC‐induced anabolic signalling. Methods Mechano‐sensitive pathways and anabolic signalling were examined immediately post or 3 h after a single ECC bout in cachectic male ApcMin/+ mice (n = 17; 16 ± 1% body weight loss). Muscle STAT3/NFκB regulation of basal and ECC‐induced anabolic signalling was also examined in an additional cohort of ApcMin/+ mice (n = 10; 16 ± 1% body weight loss) that received pyrrolidine dithiocarbamate 24 h prior to a single ECC bout. In all experiments, the left tibialis anterior performed ECC while the right tibialis anterior served as intra‐animal control. Data were analysed by Student's t‐test or two‐way repeated measures analysis of variance with Student‐Newman‐Keuls post‐hoc when appropriate. The accepted level of significance was set at P < 0.05 for all analysis. Results ApcMin/+ mice exhibited a cachectic muscle signature demonstrated by perturbed proteostasis (Ribosomal Protein S6 (RPS6), P70S6K, Atrogin‐1, and Muscle RING‐finger protein‐1 (MuRF1)), metabolic (adenosine monophosphate‐activated protein kinase, Peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PGC‐1α), and Cytochrome c oxidase subunit IV (COXIV)), and inflammatory (STAT3, NFκB, extracellular signal‐regulated kinases 1 and 2, and P38) signalling pathway regulation. Nonetheless, mechano‐sensitive signalling pathways (P38, extracellular signal‐regulated kinases 1 and 2, and Protein kinase B (AKT)) were activated immediately post‐ECC irrespective of cachexia. While cachexia did not attenuate ECC‐induced P70S6K activation, the protein synthesis induction remained suppressed compared with healthy controls. However, muscle STAT3/NFκB inhibition increased basal and ECC‐induced protein synthesis in cachectic ApcMin/+ mice. Conclusions These studies demonstrate that mechano‐sensitive signalling is maintained in cachectic skeletal muscle, but chronic STAT3/NFκB signalling serves to attenuate basal and ECC‐induced protein synthesis.

The purpose of this study was to examine the effects of inter-repetition rest (IRR) on ratings of perceived exertion (RPE) in the power clean exercise in a multiple set protocol using peak power as an indication of fatigue. Ten resistance-trained males participated in four testing sessions which consisted of determination of a one repetition maximum (1RM) in the power clean exercise (session 1) and performance of three sets of six repetitions at 80% of 1RM with 0 (P0), 20 (P20), or 40 s (P40) IRR (sessions 2–4). Fatigue during all three conditions was indicated by a significant decrease in power of 9.0% (P0), 3.0% (P20) and 2.1% (P40), respectively. Significant difference in the rate of power decrease in P40 indicates less fatigue in comparison to P0 and P20. P40 resulted in a significantly lower RPE compared to P0 and P20 (7.43 ± 0.34, 6.46 ± 0.47, and 5.30 ± 0.55, respectively). RPE increased significantly ( p  ≤ 0.01) within each set (5.26 ± 0.37, 6.46 ± 0.44, and 7.46 ± 0.53; sets 1, 2, and 3, respectively). Significant difference in average RPE between the conditions indicates that RPE is not a determinant of intensity (% of 1RM) but the rate of fatigue (decreases in peak power). In addition, the fact that RPE increased between sets 1, 2 and 3 during all conditions support the same conclusion. The results demonstrate that increasing IRR in power clean training decreases the perception of effort and is inversely related to the rate of fatigue.

Skeletal muscle wasting results from numerous pathological conditions affecting both the musculoskeletal and nervous systems. A unifying feature of these pathologies is the upregulation of members of the E3 ubiquitin ligase family, resulting in increased proteolytic degradation of target proteins. Despite the critical role of E3 ubiquitin ligases in regulating muscle mass, the specific proteins they target for degradation and the mechanisms by which they regulate skeletal muscle homeostasis remain ill-defined. Here, using zebrafish loss-of-function models combined with in vivo cell biology and proteomic approaches, we reveal a role of atrogin-1 in regulating the levels of the endoplasmic reticulum chaperone BiP. Loss of atrogin-1 resulted in an accumulation of BiP, leading to impaired mitochondrial dynamics and a subsequent loss in muscle fiber integrity. We further implicated a disruption in atrogin-1-mediated BiP regulation in the pathogenesis of Duchenne muscular dystrophy. We revealed that BiP was not only upregulated in Duchenne muscular dystrophy, but its inhibition using pharmacological strategies, or by upregulating atrogin-1, significantly ameliorated pathology in a zebrafish model of Duchenne muscular dystrophy. Collectively, our data implicate atrogin-1 and BiP in the pathogenesis of Duchenne muscular dystrophy and highlight atrogin-1's essential role in maintaining muscle homeostasis.

The development of the musculoskeletal system and its maintenance depends on the reciprocal relationship between muscle and bone. The size of skeletal muscles and the forces generated during muscle contraction are potent sources of mechanical stress on the developing skeleton, and they shape bone structure during growth. This is particularly evident in hypermuscular global myostatin (Mstn)‐null mice, where larger muscles during development increase bone mass and alter bone shape. However, whether muscle hypertrophy can similarly influence the shape of bones after the embryonic and prepubertal period is unknown. To address this issue, bone structure was assessed after inducing muscle hypertrophy in the lower hindlimbs of young‐adult C57BL/6J male mice by administering intramuscular injections of recombinant adeno‐associated viral vectors expressing follistatin (FST), a potent antagonist of Mstn. Two FST isoforms were used: the full‐length 315 amino acid isoform (FST‐315) and a truncated 288 amino acid isoform (FST‐288). In both FST‐treated cohorts, muscle hypertrophy was observed, and the anterior crest of the tibia, adjacent to the tibialis anterior muscle, was lengthened. Hypertrophy of the muscles surrounding the tibia caused the adjacent cortical shell to recede inward toward the central axis: an event driven by bone resorption adjacent to the hypertrophic muscle. The findings reveal that inducing muscle hypertrophy in mice can confer changes in bone shape in early adulthood. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Background Cancer cachexia is largely irreversible, at least via nutritional means, and responsible for 20–40% of cancer‐related deaths. Therefore, preventive measures are of primary importance; however, little is known about muscle perturbations prior to onset of cachexia. Cancer cachexia is associated with mitochondrial degeneration; yet, it remains to be determined if mitochondrial degeneration precedes muscle wasting in cancer cachexia. Therefore, our purpose was to determine if mitochondrial degeneration precedes cancer‐induced muscle wasting in tumour‐bearing mice. Methods First, weight‐stable (MinStable) and cachectic (MinCC) ApcMin/+ mice were compared with C57Bl6/J controls for mRNA contents of mitochondrial quality regulators in quadriceps muscle. Next, Lewis lung carcinoma (LLC) cells or PBS (control) were injected into the hind flank of C57Bl6/J mice at 8 week age, and tumour allowed to develop for 1, 2, 3, or 4 weeks to examine time course of cachectic development. Succinate dehydrogenase stain was used to measure oxidative phenotype in tibialis anterior muscle. Mitochondrial quality and function were assessed using the reporter MitoTimer by transfection to flexor digitorum brevis and mitochondrial function/ROS emission in permeabilized adult myofibres from plantaris. RT‐qPCR and immunoblot measured the expression of mitochondrial quality control and antioxidant proteins. Data were analysed by one‐way ANOVA with Student–Newman–Kuels post hoc test. Results MinStable mice displayed ~50% lower Pgc‐1α, Pparα, and Mfn2 compared with C57Bl6/J controls, whereas MinCC exhibited 10‐fold greater Bnip3 content compared with C57Bl6/J controls. In LLC, cachectic muscle loss was evident only at 4 weeks post‐tumour implantation. Oxidative capacity and mitochondrial content decreased by ~40% 4 weeks post‐tumour implantation. Mitochondrial function decreased by ~25% by 3 weeks after tumour implantation. Mitochondrial degeneration was evident by 2 week LLC compared with PBS control, indicated by MitoTimer red/green ratio and number of pure red puncta. Mitochondrial ROS production was elevated by ~50 to ~100% when compared with PBS at 1–3 weeks post‐tumour implantation. Mitochondrial quality control was dysregulated throughout the progression of cancer cachexia in tumour‐bearing mice. In contrast, antioxidant proteins were not altered in cachectic muscle wasting. Conclusions Functional mitochondrial degeneration is evident in LLC tumour‐bearing mice prior to muscle atrophy. Contents of mitochondrial quality regulators across ApcMin/+ and LLC mice suggest impaired mitochondrial quality control as a commonality among pre‐clinical models of cancer cachexia. Our data provide novel evidence for impaired mitochondrial health prior to cachectic muscle loss and provide a potential therapeutic target to prevent cancer cachexia.

Background. The purpose of this study was to determine the effect of two clinically relevant radiation doses on the susceptibility of mouse skeletal muscle to remodeling. Materials and methods. Alterations in muscle morphology and regulatory signaling were examined in tibialis anterior and gastrocnemius muscles after radiation doses that differed in total biological effective dose (BED). Female C57BL/6 (8-wk) mice were randomly assigned to non-irradiated control, four fractionated doses of 4 Gy (4x4 Gy; BED 37 Gy), or a single 16 Gy dose (16 Gy; BED 100 Gy). Mice were sacrificed 2 weeks after the initial radiation exposure. Results. The 16 Gy, but not 4x4 Gy, decreased total muscle protein and RNA content. Related to muscle regeneration, both 16 Gy and 4x4 Gy increased the incidence of central nuclei containing myofibers, but only 16 Gy increased the extracellular matrix volume. However, only 4x4 Gy increased muscle 4-hydroxynonenal expression. While both 16 Gy and 4x4 Gy decreased IIB myofiber mean cross-sectional area (CSA), only 16 Gy decreased IIA myofiber CSA. 16 Gy increased the incidence of small diameter IIA and IIB myofibers, while 4x4 Gy only increased the incidence of small diameter IIB myofibers. Both treatments decreased the frequency and CSA of low succinate dehydrogenase activity (SDH) fibers. Only 16 Gy increased the incidence of small diameter myofibers having high SDH activity. Neither treatment altered muscle signaling related to protein turnover or oxidative metabolism. Conclusions. Collectively, these results demonstrate that radiation dose differentially affects muscle remodeling, and these effects appear to be related to fiber type and oxidative metabolism.