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.
    Frontiers in Physiology 03/2015; 6. DOI:10.3389/fphys.2015.00063 · 3.53 Impact Factor
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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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    ABSTRACT: Treatment of neuromuscular diseases is still an unsolved problem. Evidence over the last years strongly indicates the involvement of malformation and dysfunction of neuromuscular junctions in the development of such medical conditions. Stabilization of NMJs thus seems to be a promising approach to attenuate the disease progression of muscle wasting diseases. An important pathway for the formation and maintenance of NMJs is the agrin/Lrp4/MuSK pathway. Here we demonstrate that the agrin biologic NT-1654 is capable of activating the agrin/Lrp4/MuSK system in vivo, leading to an almost full reversal of the sarcopenia-like phenotype in neurotrypsin-overexpressing (SARCO) mice. We also show that injection of NT-1654 accelerates muscle re-innervation after nerve crush. This report demonstrates that a systemically administered agrin fragment has the potential to counteract the symptoms of neuromuscular disorders.
    PLoS ONE 02/2014; 9(2):e88739. DOI:10.1371/journal.pone.0088739 · 3.23 Impact Factor
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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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    ABSTRACT: Diaphragmatic contractility is reduced in preterm lambs after lipopolysaccharide (LPS) exposure in utero. The mechanism of impaired fetal diaphragm contractility after LPS exposure is unknown. We hypothesise that in utero exposure to LPS induces a deficiency of mitochondrial complex activity and oxidative damage in the fetal diaphragm. To test this hypothesis, we used a well-established preterm ovine model of chorioamnionitis: Pregnant ewes received intra-amniotic (IA) saline or 10 mg LPS, at 2 d or 7 d prior to surgical delivery at 121 d GA (term = 150 d). The fetus was killed humanely immediately after delivery for tissue sampling. Mitochondrial fractions were prepared from the isolated diaphragm and mitochondrial electron transfer chain activities were evaluated using enzymatic assays. Oxidative stress was investigated by quantifying mitochondrial oxidative protein levels and determining antioxidant gene and protein (catalase, superoxide dismutase 2 and glutathione peroxidase 1) expression. The activity of the erythroid 2-related factor 2 (Nrf2)-mediated antioxidant signalling pathway was examined by quantifying the Nrf2 protein content of cell lysate and nuclear extract. A 2 d LPS exposure in utero significantly decreased electron transfer chain complex II and IV activity (p<0.05). A 7 d LPS exposure inhibited superoxide dismutase 2 and catalase expression at gene and protein levels, and Nrf2 pathway activity (p<0.05) compared with control and 2 d LPS groups, respectively. Diaphragm mitochondria accumulated oxidised protein after a 7 d LPS exposure. We conclude that intrauterine exposure to LPS induces mitochondrial oxidative stress and electron chain dysfunction in the fetal diaphragm, that is further exacerbated by impairment of the antioxidant signalling pathway and decreased antioxidant activity.
    PLoS ONE 09/2013; 8(9):e73457. DOI:10.1371/journal.pone.0073457 · 3.23 Impact Factor
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