Mitochondrial signaling contributes to disuse muscle atrophy

Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL 32611, USA.
AJP Endocrinology and Metabolism (Impact Factor: 4.09). 03/2012; 303(1):E31-9. DOI: 10.1152/ajpendo.00609.2011
Source: PubMed

ABSTRACT It is well established that long durations of bed rest, limb immobilization, or reduced activity in respiratory muscles during mechanical ventilation results in skeletal muscle atrophy in humans and other animals. The idea that mitochondrial damage/dysfunction contributes to disuse muscle atrophy originated over 40 years ago. These early studies were largely descriptive and did not provide unequivocal evidence that mitochondria play a primary role in disuse muscle atrophy. However, recent experiments have provided direct evidence connecting mitochondrial dysfunction to muscle atrophy. Numerous studies have described changes in mitochondria shape, number, and function in skeletal muscles exposed to prolonged periods of inactivity. Furthermore, recent evidence indicates that increased mitochondrial ROS production plays a key signaling role in both immobilization-induced limb muscle atrophy and diaphragmatic atrophy occurring during prolonged mechanical ventilation. Moreover, new evidence reveals that, during denervation-induced muscle atrophy, increased mitochondrial fragmentation due to fission is a required signaling event that activates the AMPK-FoxO3 signaling axis, which induces the expression of atrophy genes, protein breakdown, and ultimately muscle atrophy. Collectively, these findings highlight the importance of future research to better understand the mitochondrial signaling mechanisms that contribute to disuse muscle atrophy and to develop novel therapeutic interventions for prevention of inactivity-induced skeletal muscle atrophy.

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    • "Since mitochondrial exercise adaptations are observed in hibernating squirrel tissue, the concern raises whether endurance exercise damages occur as well during hibernation, such as oxidative stress formation promoted through enhanced ROS formation (Powers and Jackson, 2008). In addition, long-term immobilization has been also associated with increased mitochondrial ROS production (Powers et al., 2012). Unexpectedly, we did not find signs of increased oxidative stress formation during hibernation as revealed by unchanged oxidized mitochondrial protein levels. "
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    ABSTRACT: Skeletal muscle atrophy is a very common clinical challenge in many disuse conditions. Maintenance of muscle mass is crucial to combat debilitating functional consequences evoked from these clinical conditions. In contrast, hibernation represents a physiological state in which there is natural protection against disuse atrophy despite prolonged periods of immobilization and lack of nutrient intake. Even though peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1-α (PGC-1α) is a central mediator in muscle remodeling pathways, its role in the preservation of skeletal muscle mass during hibernation remains unclear. Since PGC-1α regulates muscle fiber type formation and mitochondrial biogenesis, we analyzed muscles of 13-lined ground squirrels. We find that animals in torpor exhibit a shift to slow-twitch Type I muscle fibers. This switch is accompanied by activation of the PGC-1α-mediated endurance exercise pathway. In addition, we observe increased antioxidant capacity without evidence of oxidative stress, a marked decline in apoptotic susceptibility, and enhanced mitochondrial abundance and metabolism. These results show that activation of the endurance exercise pathway can be achieved in vivo despite prolonged periods of immobilization, and therefore might be an important mechanism for skeletal muscle preservation during hibernation. This PGC-1α regulated pathway may be a potential therapeutic target promoting skeletal muscle homeostasis and oxidative balance to prevent muscle loss in a variety of inherited and acquired neuromuscular disease conditions.
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    • "And, how does increased ROS production affect myocyte protein metabolism and intracellular signaling pathways involved in disuse muscle atrophy ? A large body of evidence indicates that mitochondria are the primary source of ROS during chronic muscle inactivity (reviewed in Powers et al. , 2012 ). Remarkably, administration of the mitochondria-targeted antioxidant SS-31 has recently been shown to attenuate ROS production and myofiber atrophy in hind-limb muscles (Min et al. , 2011 ) and the diaphragm (Powers et al. , 2011a ) of mice subjected to cast immobilization and mechanical ventilation, respectively. "
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    ABSTRACT: Abstract Muscle loss during aging and disuse is a highly prevalent and disabling condition, but the knowledge about cellular pathways mediating muscle atrophy is still limited. Given the postmitotic nature of skeletal myocytes, the maintenance of cellular homeostasis relies on the efficiency of cellular quality control mechanisms. In this scenario, alterations in mitochondrial function are considered a major factor underlying sarcopenia and disuse muscle wasting. Damaged mitochondria not only are less bioenergetically efficient, but also generate increased amounts of reactive oxygen species, interfere with cellular quality control mechanisms, and display greater propensity to trigger apoptosis. Thus, mitochondria stand at the crossroad of signaling pathways that regulate skeletal myocyte function and viability. Studies on these pathways have sometimes provided unexpected and counterintuitive results, suggesting that they are organized into a complex, heterarchical network that is currently insufficiently understood. Untangling the complexity of such network will likely provide clinicians with novel and highly effective therapeutics to counter muscle loss associated with aging and disuse. In this review, we summarize the current knowledge on the mechanisms whereby mitochondrial dysfunction intervenes in the pathogenesis of sarcopenia and disuse atrophy, and highlight the prospect of targeting specific processes to treat these conditions.
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