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: 3.79). 03/2012; 303(1):E31-9. DOI: 10.1152/ajpendo.00609.2011
Source: PubMed


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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    • "These studies demonstrated that muscles subjected to denervation had mitochondria that were irregularly shaped and swollen (Aloisi et al., 1960; Carafoli et al., 1964; Muscatello and Patriarca, 1968) and had impaired mitochondrial coupling. Since these initial investigations, it has become well accepted that disuse muscle atrophy results in altered mitochondrial morphology and mitochondrial dysfunction (Powers et al., 2012b). Indeed, disuse atrophy disrupts the functioning of the oxidative phosphorylation system (i.e., electron transport chain), which results in the generation of superoxide (O − 2 ). "
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    ABSTRACT: Emerging evidence suggests that exercise training can provide a level of protection against disuse muscle atrophy. Endurance exercise training imposes oxidative, metabolic, and heat stress on skeletal muscle which activates a variety of cellular signaling pathways that ultimately leads to the increased expression of proteins that have been demonstrated to protect muscle from inactivity –induced atrophy. This review will highlight the effect of exercise-induced oxidative stress on endogenous enzymatic antioxidant capacity (i.e., superoxide dismutase, glutathione peroxidase, and catalase), the role of oxidative and metabolic stress on PGC1-α, and finally highlight the effect heat stress and HSP70 induction. Finally, this review will discuss the supporting scientific evidence that these proteins can attenuate muscle atrophy through exercise preconditioning.
    Full-text · Article · Mar 2015 · Frontiers in Physiology
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    • "In addition, we also observed that the loss of muscle fibers due to disintegrated NMJs was stopped and the energy metabolism was reverted back to normal as indicated by the COX staining. This finding correlates with the observations described by Powers at al., [25]: it is known that upon induced muscle atrophy in humans, e.g. by immobilization, mechanical ventilation or by denervation, mitochondrial physiologic changes and/or breakdown are key elements for specific pathways inducing fiber atrophy. A possible involvement of the agrin/Lrp4/MuSK pathway in the physiological changes of the mitochondria has already been shown by [31] demonstrating swollen and irregularly shaped mitochondria in humans suffering from MuSK-dependent myasthenia gravis. "
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    Full-text · Article · Feb 2014 · PLoS ONE
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    • "Studies of muscle weakness in adult models of muscle atrophy show that muscle fibre injury is associated with oxidative stress and/or that mitochondrial dysfunction and increased mitochondrial production of reactive oxygen species (ROS) play a key role in triggering the atrophic signals [3]–[5]. The concept of oxidative stress-induced muscle weakness is supported by evidence that mitochondria-targeted antioxidants attenuated immobilization-induced increases in mitochondrial ROS production and prevented oxidative stress, protease activation, and myofiber atrophy [6]. "
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    Full-text · Article · Sep 2013 · PLoS ONE
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