Autophagy is required to maintain muscle mass.
ABSTRACT The ubiquitin-proteasome and autophagy-lysosome pathways are the two major routes for protein and organelle clearance. In skeletal muscle, both systems are under FoxO regulation and their excessive activation induces severe muscle loss. Although altered autophagy has been observed in various myopathies, the specific role of autophagy in skeletal muscle has not been determined by loss-of-function approaches. Here, we report that muscle-specific deletion of a crucial autophagy gene, Atg7, resulted in profound muscle atrophy and age-dependent decrease in force. Atg7 null muscles showed accumulation of abnormal mitochondria, sarcoplasmic reticulum distension, disorganization of sarcomere, and formation of aberrant concentric membranous structures. Autophagy inhibition exacerbated muscle loss during denervation and fasting. Thus, autophagy flux is important to preserve muscle mass and to maintain myofiber integrity. Our results suggest that inhibition/alteration of autophagy can contribute to myofiber degeneration and weakness in muscle disorders characterized by accumulation of abnormal mitochondria and inclusions.
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ABSTRACT: It is generally believed that optimal hypertrophic and strength gains are induced through moderate- or high-intensity resistance training, equivalent to at least 60 % of an individual's 1-repetition maximum (1RM). However, recent evidence suggests that similar adaptations are facilitated when low-intensity resistance exercise (~20-50 % 1RM) is combined with blood flow restriction (BFR) to the working muscles. Although the mechanisms underpinning these responses are not yet firmly established, it appears that localized hypoxia created by BFR may provide an anabolic stimulus by enhancing the metabolic and endocrine response, and increase cellular swelling and signalling function following resistance exercise. Moreover, BFR has also been demonstrated to increase type II muscle fibre recruitment during exercise. However, inappropriate implementation of BFR can result in detrimental effects, including petechial haemorrhage and dizziness. Furthermore, as BFR is limited to the limbs, the muscles of the trunk are unable to be trained under localized hypoxia. More recently, the use of systemic hypoxia via hypoxic chambers and devices has been investigated as a novel way to stimulate similar physiological responses to resistance training as BFR techniques. While little evidence is available, reports indicate that beneficial adaptations, similar to those induced by BFR, are possible using these methods. The use of systemic hypoxia allows large groups to train concurrently within a hypoxic chamber using multi-joint exercises. However, further scientific research is required to fully understand the mechanisms that cause augmented muscular changes during resistance exercise with a localized or systemic hypoxic stimulus.Sports medicine (Auckland, N.Z.). 04/2014;
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ABSTRACT: The world's elderly population is expanding rapidly, and we are now faced with the significant challenge of maintaining or improving physical activity, independence, and quality of life in the elderly. Sarcopenia, the age-related loss of skeletal muscle mass, is characterized by a deterioration of muscle quantity and quality leading to a gradual slowing of movement, a decline in strength and power, increased risk of fall-related injury, and often, frailty. Since sarcopenia is largely attributed to various molecular mediators affecting fiber size, mitochondrial homeostasis, and apoptosis, the mechanisms responsible for these deleterious changes present numerous therapeutic targets for drug discovery. Muscle loss has been linked with several proteolytic systems, including the ubuiquitin-proteasome, lysosome-autophagy, and tumor necrosis factor (TNF)-α/nuclear factor-kappaB (NF-κB) systems. Although many factors are considered to regulate age-dependent muscle loss, this gentle atrophy is not affected by factors known to enhance rapid atrophy (denervation, hindlimb suspension, etc.). In addition, defects in Akt-mammalian target of rapamycin (mTOR) and serum response factor (SRF)-dependent signaling have been found in sarcopenic muscle. Intriguingly, more recent studies indicated an apparent functional defect in autophagy- and myostatin-dependent signaling in sarcopenic muscle. In this review, we summarize the current understanding of the adaptation of many regulators in sarcopenia.Pflügers Archiv - European Journal of Physiology 05/2014; · 4.87 Impact Factor
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ABSTRACT: Cardiomyocyte proteostasis is mediated by the ubiquitin/proteasome system (UPS) and autophagy/lysosome system and is fundamental for cardiac adaptation to both physiologic (e.g., exercise) and pathologic (e.g., pressure overload) stresses. Both the UPS and autophagy/lysosome system exhibit reduced efficiency as a consequence of aging, and dysfunction in these systems is associated with cardiomyopathies. The muscle-specific ubiquitin ligase atrogin-1 targets signaling proteins involved in cardiac hypertrophy for degradation. Here, using atrogin-1 KO mice in combination with in vivo pulsed stable isotope labeling of amino acids in cell culture proteomics and biochemical and cellular analyses, we identified charged multivesicular body protein 2B (CHMP2B), which is part of an endosomal sorting complex (ESCRT) required for autophagy, as a target of atrogin-1-mediated degradation. Mice lacking atrogin-1 failed to degrade CHMP2B, resulting in autophagy impairment, intracellular protein aggregate accumulation, unfolded protein response activation, and subsequent cardiomyocyte apoptosis, all of which increased progressively with age. Cellular proteostasis alterations resulted in cardiomyopathy characterized by myocardial remodeling with interstitial fibrosis, with reduced diastolic function and arrhythmias. CHMP2B downregulation in atrogin-1 KO mice restored autophagy and decreased proteotoxicity, thereby preventing cell death. These data indicate that atrogin-1 promotes cardiomyocyte health through mediating the interplay between UPS and autophagy/lysosome system and its alteration promotes development of cardiomyopathies.The Journal of clinical investigation 05/2014; · 15.39 Impact Factor