Mitochondrial maintenance via autophagy contributes to functional skeletal muscle regeneration and remodeling

Nichenko, Anna S.; Southern, William M.; Atuan, Mark; Luan, Jun-Na; Peissig, Kristen; Foltz, Steven J.; Beedle, Aaron M.; Warren, Gordon L.; Call, Jarrod A.

doi:10.1152/ajpcell.00066.2016

Cited by 64 publications

(71 citation statements)

References 34 publications

(45 reference statements)

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“…We speculate that this complexity reflects the degradation of specific targets (e.g., mitochondria), which is in accordance with a possible involvement of autophagy in skeletal muscle metabolic plasticity in addition to its classic role in muscle mass regulation (67,68). Recent papers suggest a crucial role for autophagy, and more specifically, mitophagy, in skeletal muscle functional regeneration (69,70).…”

Section: Discussionsupporting

confidence: 72%

Coordinated regulation of skeletal muscle mass and metabolic plasticity during recovery from disuse

et al. 2018

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Skeletal muscle regeneration after disuse is essential for muscle maintenance and involves the regulation of both mass- and metabolic plasticity-related processes. However, the relation between these processes during recovery from disuse remains unclear. In this study, we explored the potential interrelationship between the molecular regulation of muscle mass and oxidative metabolism during recovery from disuse. Molecular profiles were measured in biopsies from the vastus lateralis of healthy men after 1-leg cast immobilization and after 1 wk reloading, and in mouse gastrocnemius obtained before and after hindlimb suspension and during reloading (RL-1, -2, -3, -5, and -8 d). Cluster analysis of the human recovery response revealed correlations between myogenesis and autophagy markers in 2 clusters, which were distinguished by the presence of markers of early myogenesis, autophagosome formation, and mitochondrial turnover vs. markers of late myogenesis, autophagy initiation, and mitochondrial mass. In line with these findings, an early transient increase in B-cell lymphoma-2 interacting protein-3 and sequestosome-1 protein, and GABA type A receptor-associated protein like-1 protein and mRNA and a late increase in myomaker and myosin heavy chain-8 mRNA, microtubule-associated protein 1 light chain 3-II:I ratio, and FUN14 domain-containing-1 mRNA and protein were observed in mice. In summary, the regulatory profiles of protein, mitochondrial, and myonuclear turnover are correlated and temporally associated, suggesting a coordinated regulation of muscle mass- and oxidative metabolism-related processes during recovery from disuse.-Kneppers, A., Leermakers, P., Pansters, N., Backx, E., Gosker, H., van Loon, L., Schols, A., Langen, R., Verdijk, L. Coordinated regulation of skeletal muscle mass and metabolic plasticity during recovery from disuse.

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Section: Discussionsupporting

confidence: 72%

Coordinated regulation of skeletal muscle mass and metabolic plasticity during recovery from disuse

et al. 2018

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“…Second, mitochondrial quality is necessary for successful regeneration, as Jash et al demonstrated that restoring mitochondria with polycistronic RNAs after muscle injury can lead to greater activation and proliferation of endogenous satellite cell populations (59). Lastly, enhancing mitochondrial capacity is sufficient to accelerate recovery of muscle function suggesting that the functional quality of the mitochondrial network is important for the regeneration potential of the muscle (60). Given this evidence, it is not surprising that extensive damage to the mitochondrial network after VML would be associated with extreme loss in muscle function.…”

Section: Discussionmentioning

confidence: 99%

PGC-1α overexpression partially rescues impaired oxidative and contractile pathophysiology following volumetric muscle loss injury

Southern

Nichenko

Tehrani

et al. 2019

Preprint

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Volumetric muscle loss (VML) injury is characterized by a non-recoverable loss of muscle fibers due to ablative surgery or severe orthopaedic trauma, that results in chronic functional impairments of the soft tissue. Currently, the effects of VML on the oxidative capacity and adaptability of the remaining injured muscle are unclear. A better understanding of this pathophysiology could significantly shape how VML-injured patients and clinicians approach regenerative medicine and rehabilitation following injury. Herein, the data indicated that VML-injured muscle has diminished mitochondrial content and function (i.e. oxidative capacity), loss of mitochondrial network organization, and attenuated oxidative adaptations to exercise. However, forced PGC-1 overexpression rescued the deficits in oxidative capacity and muscle strength. This implicates physiological activation of PGC1-α as a limiting factor in VML-injured muscle adaptive capacity and provides a mechanistic target for regenerative rehabilitation approaches to address the skeletal muscle dysfunction.Oxidative capacity is a cornerstone of skeletal muscle health, and for the past 40 years, we have known that the most robust physiologic adaptation to regularly scheduled physical activity (i.e., exercise/overload training) is an increase in oxidative capacity (1,2). Improvements in muscle oxidative capacity are made possible with exercise training through adaptations affecting the density and function of the intramuscular mitochondrial network. The signaling pathways that initiate and coordinate mitochondrial improvements with exercise are complex, but advancements in molecular biology in the last two decades have revealed many of the key players involved (see for review (3)). Most notably, the transcription factor PGC-1 (peroxisome proliferator-activated receptor gamma, coactivator 1 alpha) is considered a critical molecular modulator of skeletal muscle oxidative plasticity because it regulates gene expression patterns for expansion of the mitochondrial network (i.e. mitochondrial biogenesis), angiogenesis, and motor neuron associated adaptations with exercise training(4-6). Expansion of the vasculature and mitochondrial network with exercise training enhances the functional capacity of the muscle (e.g., fatigue resistance), and in general, this physiologic type of acclimation is considered beneficial for human performance and health (7,8).Large-scale skeletal muscle trauma, such as volumetric muscle loss (VML) injury, is unique in that the muscle is not able to regenerate muscle fibers with endogenous repair systems and as a result, cannot fully recover strength. The loss of muscle function (i.e., contractility) can exceed the loss of tissue mass(9), and this permanent functional deficit leaves patients with lifelong disability(10) for which there is currently no corrective physical rehabilitation guidelines. Furthermore, the extent to which the remaining skeletal muscle can adapt to rehabilitation is unclear. Recent preclinical work has investigated various...

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“…Given the proximity to the primary site of mtROS production, mitochondrial macromolecules are especially vulnerable to oxidative damage [61]. Accumulation of damaged mitochondrial proteins contributes to mitochondrial dysfunction, which effectively impairs tissue function and recovery [31]. Mitochondrial respiration can be regulated by redox-based protein modifications of cysteine residues.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial protein S-nitrosation protects against ischemia reperfusion-induced denervation at neuromuscular junction in skeletal muscle

Wilson

Drake

Cui

et al. 2018

Free Radical Biology and Medicine

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Deterioration of neuromuscular junction (NMJ) integrity and function is causal to muscle atrophy and frailty, ultimately hindering quality of life and increasing the risk of death. In particular, NMJ is vulnerable to ischemia reperfusion (IR) injury when blood flow is restricted followed by restoration. However, little is known about the underlying mechanism(s) and hence the lack of effective interventions. New evidence suggests that mitochondrial oxidative stress plays a causal role in IR injury, which can be precluded by enhancing mitochondrial protein S-nitrosation (SNO). To elucidate the role of IR and mitochondrial protein SNO in skeletal muscle, we utilized a clinically relevant model and showed that IR resulted in significant muscle and motor nerve injuries with evidence of elevated muscle creatine kinase in the serum, denervation at NMJ, myofiber degeneration and regeneration, as well as muscle atrophy. Interestingly, we observed that neuromuscular transmission improved prior to muscle recovery, suggesting the importance of the motor nerve in muscle functional recovery. Injection of a mitochondria-targeted S-nitrosation enhancing agent, MitoSNO, into ischemic muscle prior to reperfusion reduced mitochondrial oxidative stress in the motor nerve and NMJ, attenuated denervation at NMJ, and resulted in accelerated functional recovery of the muscle. These findings demonstrate that enhancing mitochondrial protein SNO protects against IR-induced denervation at NMJ in skeletal muscle and accelerates functional regeneration. This could be an efficacious intervention for protecting neuromuscular injury under the condition of IR and other related pathological conditions.

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Mitochondrial maintenance via autophagy contributes to functional skeletal muscle regeneration and remodeling

Cited by 64 publications

References 34 publications

Coordinated regulation of skeletal muscle mass and metabolic plasticity during recovery from disuse

Coordinated regulation of skeletal muscle mass and metabolic plasticity during recovery from disuse

PGC-1α overexpression partially rescues impaired oxidative and contractile pathophysiology following volumetric muscle loss injury

Mitochondrial protein S-nitrosation protects against ischemia reperfusion-induced denervation at neuromuscular junction in skeletal muscle

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