Oxidative stress and disuse muscle atrophy.

Skeletal muscle inactivity is associated with a loss of muscle protein and reduced force-generating capacity. This disuse-induced muscle atrophy results from both increased proteolysis and decreased protein synthesis. Investigations of the cell signaling pathways that regulate disuse muscle atrophy have increased our understanding of this complex process. Emerging evidence implicates oxidative stress as a key regulator of cell signaling pathways, leading to increased proteolysis and muscle atrophy during periods of prolonged disuse. This review will discuss the role of reactive oxygen species in the regulation of inactivity-induced skeletal muscle atrophy. The specific objectives of this article are to provide an overview of muscle proteases, outline intracellular sources of reactive oxygen species, and summarize the evidence that connects oxidative stress to signaling pathways contributing to disuse muscle atrophy. Moreover, this review will also discuss the specific role that oxidative stress plays in signaling pathways responsible for muscle proteolysis and myonuclear apoptosis and highlight gaps in our knowledge of disuse muscle atrophy. By presenting unresolved issues and suggesting topics for future research, it is hoped that this review will serve as a stimulus for the expansion of knowledge in this exciting field.     

Redox regulation of diaphragm proteolysis during mechanical ventilation

Prevention of oxidative stress via antioxidants attenuates diaphragm myofiber atrophy associated with mechanical ventilation (MV). However, the specific redox-sensitive mechanisms responsible for this remain unknown. We tested the hypothesis that regulation of skeletal muscle proteolytic activity is a critical site of redox action during MV. Sprague-Dawley rats were assigned to five experimental groups: 1) control, 2) 6 h of MV, 3) 6 h of MV with infusion of the antioxidant Trolox, 4) 18 h of MV, and 5) 18 h of MV with Trolox. Trolox did not attenuate MV-induced increases in diaphragmatic levels of ubiquitin-protein conjugation, polyubiquitin mRNA, and gene expression of proteasomal subunits (20S proteasome alpha-subunit 7, 14-kDa E2, and proteasome-activating complex PA28). However, Trolox reduced both chymotrypsin-like and peptidylglutamyl peptide hydrolyzing (PGPH)-like 20S proteasome activities in the diaphragm after 18 h of MV. In addition, Trolox rescued diaphragm myofilament protein concentration (mug/mg muscle) and the percentage of easily releasable myofilament protein independent of alterations in ribosomal capacity for protein synthesis. In summary, these data are consistent with the notion that the protective effect of antioxidants on the diaphragm during MV is due, at least in part, to decreasing myofilament protein substrate availability to the proteasome.     

Exercise protects against doxorubicin-induced markers of autophagy signaling in skeletal muscle

Doxorubicin (DOX) is an effective antitumor agent used in cancer treatment. Unfortunately, DOX is also toxic to skeletal muscle and can result in significant muscle wasting. The cellular mechanism(s) by which DOX induces toxicity in skeletal muscle fibers remains unclear. Nonetheless, DOX-induced toxicity is associated with increased generation of reactive oxygen species, oxidative damage, and activation of the calpain and caspase-3 proteolytic systems within muscle fibers. It is currently unknown if autophagy, a proteolytic system that can be triggered by oxidative stress, is activated in skeletal muscles following DOX treatment. Therefore, we tested the hypothesis that systemic administration of DOX leads to increased expression of autophagy markers in the rat soleus muscle. Our results reveal that DOX administration results in increased muscle mRNA levels and/or protein abundance of several important autophagy proteins, including: Beclin-1, Atg12, Atg7, LC3, LC3II-to-LCI ratio, and cathepsin L. Furthermore, given that endurance exercise increases skeletal muscle antioxidant capacity and protects muscle against DOX-induced oxidative stress, we performed additional experiments to determine whether exercise training before DOX administration would attenuate DOX-induced increases in expression of autophagy genes. Our results clearly show that exercise can protect skeletal muscle from DOX-induced expression of autophagy genes. Collectively, our findings indicate that DOX administration increases the expression of autophagy genes in skeletal muscle, and that exercise can protect skeletal muscle against DOX-induced activation of autophagy.     

Mechanical ventilation promotes redox status alterations in the diaphragm.

Oxidative stress is an important mediator of diaphragm muscle atrophy and contractile dysfunction during prolonged periods of controlled mechanical ventilation (MV). To date, specific details related to the impact of MV on diaphragmatic redox status remain unknown. To fill this void, we tested the hypothesis that MV-induced diaphragmatic oxidative stress is the consequence of both an elevation in intracellular oxidant production in conjunction with a decrease in the antioxidant buffering capacity. Adult rats were assigned to one of two experimental groups: 1) control or 2) 12 h of MV. Compared with controls, diaphragms from MV animals demonstrated increased oxidant production, diminished total antioxidant capacity, and decreased glutathione levels. Heme oxygenase-1 (HO-1) mRNA and protein levels increased (23.0- and 5.1-fold, respectively) following MV. Thioredoxin reductase-1 and manganese superoxide dismutase mRNA levels were also increased in the diaphragm following MV (2.4- and 1.6-fold, respectively), although no change was detected in the levels of either protein. Furthermore, copper-zinc superoxide dismutase and glutathione peroxidase mRNA were not altered following MV, although protein content decreased -1.3- and -1.7-fold, respectively. We conclude that MV promotes increased oxidant production and impairment of key antioxidant defenses in the diaphragm; collectively, these changes contribute to the MV-induced oxidative stress in this key inspiratory muscle.     

Mechanisms of disuse muscle atrophy: role of oxidative stress

Prolonged periods of skeletal muscle inactivity lead to a loss of muscle protein and strength. Advances in cell biology have progressed our understanding of those factors that contribute to muscle atrophy. To this end, abundant evidence implicates oxidative stress as a potential regulator of proteolytic pathways leading to muscle atrophy during periods of prolonged disuse. This review will address the role of reactive oxygen species and oxidative stress as potential contributors to the process of disuse-mediated muscle atrophy. The first section of this article will discuss our current understanding of muscle proteases, sources of reactive oxygen in muscle fibers, and the evidence linking oxidative stress to disuse muscle atrophy. The second section of this review will highlight gaps in our knowledge relative to the specific role of oxidative stress in the regulation of disuse muscle atrophy. By discussing unresolved issues and suggesting topics for future research, it is hoped that this review will serve as a stimulus for the expansion of knowledge in this exciting field.