Role of PGC-1α during acute exercise-induced autophagy and mitophagy in skeletal muscle

Abstract

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 ...

Molecular Basis of Exercise-Induced Skeletal Muscle Mitochondrial Biogenesis: Historical Advances, Current Knowledge, and Future Challenges

“…Alternatively, automatic degradation following mRNA synthesis may ensure that tight control of mitochondrial biogenesis is maintained at all times to avoid excessive protein translation. Mitochondrial degradation through "mitophagy" may lead to a new era of research of how exercise may promote mitochondrial degradation as a "quality control" measure to facilitate regeneration as previously shown in rodents through a PGC1a-dependent manner (Vainshtein et al 2015). Furthermore, mitochondrial biogenesis likely involves an extensive remodeling process whereby mitochondria are formed into a tubular reticulum particularly in intermyofibrillar mitochondria that shape them around the myofibrils (Ogata and Yamasaki 1997), which likely optimizes spatial distribution of energy.…”

Mitochondrial quality control in the diabetic heart

“…This may account for the ability of PGC-1α to enhance the elimination of HTT aggregates in a Huntington disease model [169] and to coordinately upregulate mitochondrial biogenesis and mitophagy in skeletal muscle [170, 171]. However, how PGC-1α regulates mitophagy in the heart remains unknown.…”

Effects of skeletal muscle energy availability on protein turnover responses to exercise

“…Endurance exercise training can induce autophagy, and, appropriately, intracellular energetic stress elicited by exercise seems to be the nexus for autophagy induction, as ultra-endurance exercise (Jamart et al, 2012a,b), running to exhaustion (Pagano et al, 2014;Vainshtein et al, 2015b) and exercise commenced when fasted (Jamart et al, 2013;Møller et al, 2015) all upregulate autophagic signalling processes. However, in well-trained human skeletal muscle there is no synergistic effect of prior fasting on autophagy signalling compared with commencing the exercise bout in the fed state, with exercise intensity mitigating the largest autophagic response to contraction (Schwalm et al, 2015).…”

“…Early work by Salminen and Vihko (1984) using electron micrography of rodent skeletal muscle revealed autophagic vacuoles, presumably autophagosomes, engulfing partly degraded mitochondria after strenuous exercise (9 h uphill running). More recent evidence demonstrates that Parkin, an E3 ubiquitin ligase that tags mitochondrial substrates for autophagosomal sequestration, and light chain 3b-II (LC3b-II), a marker of autophagosome biogenesis, localize to rodent skeletal muscle mitochondria after running to exhaustion (Vainshtein et al, 2015b).…”