title: Role of PGC-1α during acute exercise-induced autophagy and mitophagy in skeletal muscle.
abstract: 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-γ coactivator-1α (PGC-1α). 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-1α 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-1α knockout (KO) animals. Deletion of PGC-1α 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-1α. We also identified Niemann-Pick C1, a transmembrane protein involved in lysosomal lipid trafficking, as a target of PGC-1α 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-1α.
authors: Muscle Health Research Centre, School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada.
authors: Anna
authors: A
authors: Vainshtein
authors: Muscle Health Research Centre, School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada.
authors: Liam D
authors: LD
authors: Tryon
authors: Muscle Health Research Centre, School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada.
authors: Marion
authors: M
authors: Pauly
authors: Muscle Health Research Centre, School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada dhood@yorku.ca.
authors: David A
authors: DA
authors: Hood
mesh_terms: D000138:Acidosis / Q000209:etiology / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D047908:Intracellular Signaling Peptides and Proteins; D019344:Lactic Acid / Q000097:blood; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008931:Mitochondria, Muscle / Q000378:metabolism* / Q000473:pathology; D063306:Mitophagy; D009119:Muscle Contraction; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D000077296:Niemann-Pick C1 Protein; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D005082:Physical Exertion; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D015415:Biomarkers; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D011506:Proteins; D012333:RNA, Messenger; C484068:Tcfeb protein, mouse; D014157:Transcription Factors; D019344:Lactic Acid
keywords: Niemann-Pick C1; biogenesis; endurance; mitochondria; physical activity