L muscle weakness can increase the duration of hospitalization, result in exercise limitation, and contribute to a poor quality of life. Importantly, skeletal muscle atrophy is also associated with increased morbidity and mortality of patients. Therefore, improving our understanding of the mechanism(s) responsible for skeletal muscle weakness and fatigue in patients is a required first step to develop clinical protocols to prevent these skeletal muscle problems. This review will highlight the consequences and potential mechanisms responsible for skeletal muscle atrophy and fatigue in patients experiencing acute critical illness, cancer, chronic inflammatory diseases, and neurological disorders....

The production of reactive oxygen species in skeletal muscle is linked with muscle fatigue. This study investigated the effects of the antioxidant compound N-acetylcysteine (NAC) on muscle cysteine, cystine, and glutathione and on time to fatigue during prolonged, submaximal exercise in endurance athletes. Eight men completed a double-blind, crossover study, receiving NAC or placebo before and during cycling for 45 min at 71% peak oxygen consumption (V̇o_2 peak) and then to fatigue at 92% V̇o_2 peak. NAC was intravenously infused at 125 mg·kg⁻¹·h⁻¹ for 15 min and then at 25 mg·kg⁻¹·h⁻¹ for 20 min before and throughout exercise. Arterialized venous blood was analyzed for NAC, glutathione status, and cysteine concentration. A vastus lateralis biopsy was taken preinfusion, at 45 min of exercise, and at fatigue and was analyzed for NAC, total glutathione (TGSH), reduced glutathione (GSH), cysteine, and cystine. Time to fatigue at 92% V̇o_2 peak was reproducible in preliminary trials (coefficient of variation 5.6 ± 0.6%) and with NAC was enhanced by 26.3 ± 9.1% (NAC 6.4 ± 0.6 min vs. Con 5.3 ± 0.7 min; P < 0.05). NAC increased muscle total and reduced NAC at both 45 min and fatigue ( P < 0.005). Muscle cysteine and cystine were unchanged during Con, but were elevated above preinfusion levels with NAC ( P < 0.001). Muscle TGSH ( P < 0.05) declined and muscle GSH tended to decline ( P = 0.06) during exercise. Both were greater with NAC ( P < 0.05). Neither exercise nor NAC affected whole blood TGSH. Whereas blood GSH was decreased and calculated oxidized glutathione increased with exercise ( P < 0.05), both were unaffected by NAC. In conclusion, NAC improved performance in well-trained individuals, with enhanced muscle cysteine and GSH availability a likely mechanism.

In models of cancer cachexia, inhibiting type IIB activin receptors (ActRIIBs) reverse muscle wasting and prolongs survival, even with continued tumor growth. ActRIIB mediates signaling of numerous TGF‐β proteins; of these, we demonstrate that activins are the most potent negative regulators of muscle mass. To determine whether activin signaling in the absence of tumor‐derived factors induces cachexia, we used recombinant serotype 6 adeno‐associated virus (rAAV6) vectors to increase circulating activin A levels in C57BL/6 mice. While mice injected with control vector gained ~10% of their starting body mass (3.8±0.4 g) over 10 wk, mice injected with increasing doses of rAAV6:activin A exhibited weight loss in a dose‐dependent manner, to a maximum of –12.4% (–4.2±1.1 g). These reductions in body mass in rAAV6:activin‐injected mice correlated inversely with elevated serum activin A levels (7‐ to 24‐fold). Mechanistically, we show that activin A reduces muscle mass and function by stimulating the ActRIIB pathway, leading to deleterious consequences, including increased transcription of atrophy‐related ubiquitin ligases, decreased Akt/mTOR‐mediated protein synthesis, and a profibrotic response. Critically, we demonstrate that the muscle wasting and fibrosis that ensues in response to excessive activin levels is fully reversible. These findings highlight the therapeutic potential of targeting activins in cachexia.—Chen, J. L., Walton, K. L., Winbanks, C. E., Murphy, K. T., Thomson, R. E., Makanji, Y., Qian, H., Lynch, G. S., Harrison, C. A., Gregorevic, P. Elevated expression of activins promotes muscle wasting and cachexia. FASEB J. 28, 28–1711 (1723). www.fasebj.org

Sarcopenia is the progressive loss of skeletal muscle mass and function with advancing age, leading to reduced mobility and quality of life. We tested the hypothesis that antibody‐directed myostatin inhibition would attenuate the decline in mass and function of muscles of aged mice and that apoptosis would be reduced. Eighteen‐month‐old C57BL/6 mice were treated for 14 wk with a once‐weekly injection of saline (control, n =9) or a mouse chimera of anti‐human myostatin antibody (PF‐354, 10 mg/kg; n =12). PF‐354 prevented the age‐related reduction in body mass and increased soleus, gastrocnemius, and quadriceps muscle mass ( P <0.05). PF‐354 increased fiber cross‐sectional area by 12% and enhanced maximum in situ force of tibialis anterior (TA) muscles by 35% ( P <0.05). PF‐354 increased the proportion of type IIa fibers by 114% ( P <0.01) and enhanced activity of oxidative enzymes (SDH) by 39% ( P <0.01). PF‐354 reduced markers of apoptosis in TA muscle cross‐sections by 56% ( P <0.03) and reduced caspase3 mRNA by 65% ( P <0.04). Antibody‐directed myostatin inhibition attenuated the decline in mass and function of muscles of aging mice, in part, by reducing apoptosis. These observations identify novel roles for myostatin in regulation of muscle mass and highlight the therapeutic potential of antibody‐directed myostatin inhibition for sarcopenia.—Murphy, K. T., Koopman, R., Naim, T., Léger, B., Trieu, J., Ibebunjo, C. Lynch, G. S. Antibody‐directed myostatin inhibition in 21‐mo‐old mice reveals novel roles for myostatin signaling in skeletal muscle structure and function. FASEB J . 24, 4433–4442 (2010). www.fasebj.org