Physical exercise stimulates autophagy in normal skeletal muscles but is detrimental for collagen VI-deficient muscles (original) (raw)
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Autophagy is essential to support skeletal muscle plasticity in response to endurance exercise
American journal of physiology. Regulatory, integrative and comparative physiology, 2014
Physical exercise is a stress that can substantially modulate cellular signaling mechanisms to promote morphological and metabolic adaptations. Skeletal muscle protein and organelle turnover is dependent on two major cellular pathways: Forkhead box class O proteins (FOXO) transcription factors that regulate two main proteolytic systems, the ubiquitin-proteasome, and the autophagy-lysosome systems, including mitochondrial autophagy, and the MTORC1 signaling associated with protein translation and autophagy inhibition. In recent years, it has been well documented that both acute and chronic endurance exercise can affect the autophagy pathway. Importantly, substantial efforts have been made to better understand discrepancies in the literature on its modulation during exercise. A single bout of endurance exercise increases autophagic flux when the duration is long enough, and this response is dependent on nutritional status, since autophagic flux markers and mRNA coding for actors invol...
Journal of Molecular Medicine, 2014
Metabolic homeostasis is essential for cellular survival and proper tissue function. Multi-systemic metabolic regulation is therefore vital for good health. A number of tissues have the task of maintaining appropriate metabolism, and skeletal muscle is the most abundant of them. Muscle possesses a remarkable plasticity and is able to rapidly adapt to changes in energetic demands by fine-tuning the balance between catabolic and anabolic processes. Autophagy is a catabolic process responsible for the degradation of protein aggregates and damaged organelles, through the autophagosome-lysosome system. Proper regulation of autophagy flux is fundamental for organism homeostasis under physiological conditions and even more in response to metabolic stress, such as during physical activity and nutritional deficits. Both deficient and excessive autophagy are harmful for health and have devastating consequences in a myriad of pathologies. The regulation of autophagy flux in various tissues, and in particular in skeletal muscle, is of great importance for health and tissue homeostasis and represents a feasible mechanism by which physical exercise exerts its beneficial effects on muscle and whole body metabolism. This review is focused on the key molecular mechanisms regulating macromolecule and organelle turnover in muscle during alterations in nutrient availability and energetic demands, as well as their involvement in disease pathogenesis.
Autophagy in health and disease. 3. Involvement of autophagy in muscle atrophy
AJP: Cell Physiology, 2010
Loss of muscle mass aggravates a variety of diseases, and understanding the molecular mechanisms that control muscle wasting is critical for developing new therapeutic approaches. Weakness is caused by loss of muscle proteins, and recent studies have underlined a major role for the autophagy-lysosome system in regulating muscle mass. Some key components of the autophagy machinery are transcriptionally upregulated during muscle wasting, and their induction precedes muscle loss. However, it is unclear whether autophagy is detrimental, causing atrophy, or beneficial, promoting survival during catabolic conditions. This review discusses recent findings on signaling pathways regulating autophagy.
FEBS Letters, 2010
Muscle mass represents 40-50% of the human body and, in mammals, is one of the most important sites for the control of metabolism. Moreover, during catabolic conditions, muscle proteins are mobilized to sustain gluconeogenesis in the liver and to provide alternative energy substrates for organs. However, excessive protein degradation in the skeletal muscle is detrimental for the economy of the body and it can lead to death. The ubiquitin-proteasome and autophagy-lysosome systems are the major proteolytic pathways of the cell and are coordinately activated in atrophying muscles. However, the role and regulation of the autophagic pathway in skeletal muscle is still largely unknown. This review will focus on autophagy and discuss its beneficial or detrimental role for the maintenance of muscle mass.
Autophagy Is Required to Maintain Muscle Mass
Cell Metabolism, 2009
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.
Autophagy, 2015
Chaperone-assisted selective autophagy (CASA) is a tension-induced degradation pathway essential for muscle maintenance. Impairment of CASA causes childhood muscle dystrophy and cardiomyopathy. However, the importance of CASA for muscle function in healthy individuals has remained elusive so far. Here we describe the impact of strength training on CASA in a group of healthy and moderately trained men. We show that strenuous resistance exercise causes an acute induction of CASA in affected muscles to degrade mechanically damaged cytoskeleton proteins. Moreover, repeated resistance exercise during 4 wk of training led to an increased expression of CASA components. In human skeletal muscle, CASA apparently acts as a central adaptation mechanism that responds to acute physical exercise and to repeated mechanical stimulation.
Mitochondrial dysfunction and autophagy responses to skeletal muscle stress
2019
Autophagy plays an important role in mitochondrial maintenance, yet many details of skeletal muscle autophagic activity are unresolved in the context of muscle stress and/or damage. Skeletal muscles from mice were stressed either by fatiguing contractions, eccentric contractioninduced injury (ECCI), or freeze injury (FI) to establish a timeline of mitochondrial function and autophagy induction after different forms of muscle stress. Only FI was sufficient to elicit a reduction in mitochondrial function (-88%, p=0.006), yet both ECCI and FI resulted in greater autophagy-related protein content (28-fold, p0.008) suggesting a tunable autophagic response. Muscles from another cohort of mice were used to determine specific forms of autophagy, i.e., flux and mitochondrial-specific, in response to muscle damage. Mitochondrial-specific autophagy was evident by accumulation of autophagy-related proteins in mitochondrial-enriched muscle fractions following FI (37-fold, p=0.017); however, autophagy flux, assessed by LC3II accumulation with the lysosomal inhibitor chloroquine, was insignificant suggesting a physiological bottleneck in the clearance of dysfunctional organelles following FI. Ulk1 musclespecific knockout (Ulk1 MKO) mice were used to determine if autophagy is necessary for the recovery of mitochondrial function after muscle damage. Ulk1 MKO mice were weaker (-12%, p=0.012) and demonstrated altered satellite cell dynamics (e.g., proliferation) during muscle regeneration after FI compared to littermate control mice, but determination of autophagy necessity for the recovery of mitochondrial function was inconclusive. This study concludes that autophagy is a tunable cellular response to muscle damaging stress and may influence muscle fiber regeneration through interaction with satellite cells.
Nature Medicine, 2010
Autophagy is crucial in the turnover of cell components, and clearance of damaged organelles by the autophagic-lysosomal pathway is essential for tissue homeostasis. Defects of this degradative system have a role in various diseases, but little is known about autophagy in muscular dystrophies. We have previously found that muscular dystrophies linked to collagen VI deficiency show dysfunctional mitochondria and spontaneous apoptosis, leading to myofiber degeneration. Here we demonstrate that this persistence of abnormal organelles and apoptosis are caused by defective autophagy. Skeletal muscles of collagen VI-knockout (Col6a1 −/− ) mice had impaired autophagic flux, which matched the lower induction of beclin-1 and BCL-2/adenovirus E1Binteracting protein-3 (Bnip3) and the lack of autophagosomes after starvation. Forced activation of autophagy by genetic, dietary and pharmacological approaches restored myofiber survival and ameliorated the dystrophic phenotype of Col6a1 −/− mice. Furthermore, muscle biopsies from subjects with Bethlem myopathy or Ullrich congenital muscular dystrophy had reduced protein amounts of beclin-1 and Bnip3. These findings indicate that defective activation of the autophagic machinery is pathogenic in some congenital muscular dystrophies.