Vainshtein A, Tryon LD, Pauly M, Hood DA. Role of PGC-1␣ during acute exercise-induced autophagy and mitophagy in skeletal muscle. Am J Physiol Cell Physiol 308: C710 -C719, 2015. First published February 11, 2015 doi:10.1152/ajpcell.00380.2014.-Regular exercise leads to systemic metabolic benefits, which require remodeling of energy resources in skeletal muscle. During acute exercise, the increase in energy demands initiate mitochondrial biogenesis, orchestrated by the transcriptional coactivator peroxisome proliferator-activated receptor-␥ coactivator-1␣ (PGC-1␣). Much less is known about the degradation of mitochondria following exercise, although new evidence implicates a cellular recycling mechanism, autophagy/mitophagy, in exercise-induced adaptations. How mitophagy is activated and what role PGC-1␣ plays in this process during exercise have yet to be evaluated. Thus we investigated autophagy/mitophagy in muscle immediately following an acute bout of exercise or 90 min following exercise in wild-type (WT) and PGC-1␣ knockout (KO) animals. Deletion of PGC-1␣ resulted in a 40% decrease in mitochondrial content, as well as a 25% decline in running performance, which was accompanied by severe acidosis in KO animals, indicating metabolic distress. Exercise induced significant increases in gene transcripts of various mitochondrial (e.g., cytochrome oxidase subunit IV and mitochondrial transcription factor A) and autophagy-related (e.g., p62 and light chain 3) genes in WT, but not KO, animals. Exercise also resulted in enhanced targeting of mitochondria for mitophagy, as well as increased autophagy and mitophagy flux, in WT animals. This effect was attenuated in the absence of PGC-1␣. We also identified Niemann-Pick C1, a transmembrane protein involved in lysosomal lipid trafficking, as a target of PGC-1␣ that is induced with exercise. These results suggest that mitochondrial turnover is increased following exercise and that this effect is at least in part coordinated by PGC-1␣.Anna Vainshtein received the AJP-Cell 2015 Paper of the Year award. Listen to a podcast with Anna Vainshtein and coauthor David A. Hood at http://ajpcell.podbean.com/e/ajp-cell-paper-of-the-year-2015-award-podcast/. biogenesis; endurance; mitochondria; Niemann-Pick C1; physical activity THE MERITS OF PHYSICAL ACTIVITY are numerous and well documented. Regular exercise leads to improved cardiovascular health, cognition, metabolism, oxidative capacity, and fatigue resistance, among many other beneficial consequences. Moreover, increased contractile activity is also protective of muscle mass and function under a myriad of pathologies. Although alterations in skeletal muscle metabolism, as well as its secretome, have been documented to contribute to the pleiotropic benefits of regular exercise, the molecular mechanism underpinning these adaptations remains unclear.Skeletal muscle possesses a remarkable capacity to adapt to alterations in contractile activity, a property referred to as muscle plasticity. This type of cellular remodeling often ...

Aging muscle exhibits a progressive decline in mass and strength, known as sarcopenia, and a decrease in the adaptive response to contractile activity. The molecular mechanisms mediating this reduced plasticity have yet to be elucidated. The purposes of this study were 1) to determine whether denervation-induced muscle disuse would increase the expression of autophagy genes and 2) to examine whether selective autophagy pathways (mitophagy) are altered in aged animals. Denervation reduced muscle mass in young and aged animals by 24 and 16%, respectively. Moreover, young animals showed a 50% decrease in mitochondrial content following denervation, an adaptation that was not matched by aged animals. Basal autophagy protein expression was higher in aged animals, whereas young animals exhibited a greater induction of autophagy proteins following denervation. Localization of LC3II, Parkin, and p62 was significantly increased in the mitochondrial fraction of young and aged animals following denervation. Moreover, the unfolded protein response marker CHOP and the mitochondrial dynamics protein Fis1 were increased by 17-and 2.5-fold, respectively, in aged animals. Lipofuscin granules within lysosomes were evident with aging and denervation. Thus reductions in the adaptive plasticity of aged muscle are associated with decreases in disuse-induced autophagy. These data indicate that the expression of autophagy proteins and their localization to mitochondria are not decreased in aged muscle; however, the induction of autophagy in response to disuse, along with downstream events such as lysosome function, is impaired. This may contribute to an accumulation of dysfunctional mitochondria in aged muscle. reactive oxygen species; muscle atrophy; mitochondria; mitophagy; apoptosis SKELETAL MUSCLE IS A REMARKABLY plastic tissue that undergoes a striking transformation in response to decreases in contractile activity. This distinctive response is attributable to the multinucleated composition of muscle fibers and the coordinated activation of several catabolic signaling pathways. Although muscle retains its adaptability throughout the life of an organism, tissue malleability is reduced with advancing age (4, 22). Aged muscle is further affected by an age-associated loss of skeletal muscle mass and strength, a condition known as sarcopenia (8,22,42). Although the precise cellular mechanisms responsible for mediating sarcopenia have yet to be fully elucidated, several studies have implicated decreases in mitochondrial function and a corresponding increase in mitochondrially mediated cell death (apoptosis) as factors contributing to this age-induced decline (4, 8). Indeed, mitochondrially mediated apoptosis can be activated by increases in reactive oxygen species (ROS), which have also been associated with several other deleterious effects, including the oxidation of mitochondrial DNA, lipids, and proteins (10, 39). Our laboratory has shown that mitochondria from aged muscle generate more ROS, possess a lower mitochondrial membrane pot...

BackgroundAlterations in skeletal muscle contractile activity necessitate an efficient remodeling mechanism. In particular, mitochondrial turnover is essential for tissue homeostasis during muscle adaptations to chronic use and disuse. While mitochondrial biogenesis appears to be largely governed by the transcriptional co-activator peroxisome proliferator co-activator 1 alpha (PGC-1α), selective mitochondrial autophagy (mitophagy) is thought to mediate organelle degradation. However, whether PGC-1α plays a direct role in autophagy is currently unclear.MethodsTo investigate the role of the co-activator in autophagy and mitophagy during skeletal muscle remodeling, PGC-1α knockout (KO) and overexpressing (Tg) animals were unilaterally denervated, a common model of chronic muscle disuse.ResultsAnimals lacking PGC-1α exhibited diminished mitochondrial density alongside myopathic characteristics reminiscent of autophagy-deficient muscle. Denervation promoted an induction in autophagy and lysosomal protein expression in wild-type (WT) animals, which was partially attenuated in KO animals, resulting in reduced autophagy and mitophagy flux. PGC-1α overexpression led to an increase in lysosomal capacity as well as indicators of autophagy flux but exhibited reduced localization of LC3II and p62 to mitochondria, compared to WT animals. A correlation was observed between the levels of the autophagy-lysosome master regulator transcription factor EB (TFEB) and PGC-1α in muscle, supporting their coordinated regulation.ConclusionsOur investigation has uncovered a regulatory role for PGC-1α in mitochondrial turnover, not only through biogenesis but also via degradation using the autophagy-lysosome machinery. This implies a PGC-1α-mediated cross-talk between these two opposing processes, working to ensure mitochondrial homeostasis during muscle adaptation to chronic disuse.Electronic supplementary materialThe online version of this article (doi:10.1186/s13395-015-0033-y) contains supplementary material, which is available to authorized users.

While the formation of myelin by oligodendrocytes is critical for the function of the central nervous system, the molecular mechanism controlling oligodendrocyte differentiation remains largely unknown. Here we identify G protein-coupled receptor 37 (GPR37) as an inhibitor of late-stage oligodendrocyte differentiation and myelination. GPR37 is enriched in oligodendrocytes and its expression increases during their differentiation into myelin forming cells. Genetic deletion of Gpr37 does not affect the number of oligodendrocyte precursor cells, but results in precocious oligodendrocyte differentiation and hypermyelination. The inhibition of oligodendrocyte differentiation by GPR37 is mediated by suppression of an exchange protein activated by cAMP (EPAC)-dependent activation of Raf-MAPK-ERK1/2 module and nuclear translocation of ERK1/2. Our data suggest that GPR37 regulates central nervous system myelination by controlling the transition from early-differentiated to mature oligodendrocytes.

Abbreviations: ACACA, acetyl-CoA carboxylase alpha; ATG7, autophagy-related 7; BNIP3, BCL2/adenovirus E1B 19 kDa interacting protein 3; FDB, flexor digitorum brevis; MAP1LC3A, microtubule-associated protein 1 light chain 3; NAC, N-acetylcysteine; PARK2, parkin RBR E3 ubiquitin protein ligase; PRKAA1, protein kinase AMP-activated, alpha 1 catalytic subunit; ROS, reactive oxygen species; SQSTM1, sequestosome 1; TA, tibialis anterior; TMRM, tetramethylrhodamine, methyl ester.Physical activity has been recently documented to play a fundamental physiological role in the regulation of autophagy in several tissues. It has also been reported that autophagy is required for exercise itself and for traininginduced adaptations in glucose homeostasis. These autophagy-mediated metabolic improvements are thought to be largely dependent on the activation of the metabolic sensor PRKAA1/AMPK. However, it is unknown whether these important benefits stem from systemic adaptations or are due solely to alterations in skeletal muscle metabolism. To address this we utilized inducible, muscle-specific, atg7 knockout mice that we have recently generated. Our findings indicate that acute inhibition of autophagy in skeletal muscle just prior to exercise does not have an impact on physical performance, PRKAA1 activation, or glucose homeostasis. However, we reveal that autophagy is critical for the preservation of mitochondrial function during damaging muscle contraction. This effect appears to be gender specific affecting primarily females. We also establish that basal oxidative stress plays a crucial role in mitochondrial maintenance during normal physical activity. Therefore, autophagy is an adaptive response to exercise that ensures effective mitochondrial quality control during damaging physical activity.