title: PGC-1α modulates denervation-induced mitophagy in skeletal muscle.
abstract: BACKGROUND
  Alterations 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.
  
  
  METHODS
  To 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.
  
  
  RESULTS
  Animals 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.
  
  
  CONCLUSIONS
  Our 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.
authors.affiliation: Muscle Health Research Centre, School of Kinesiology and Health Science, York University, 4700 Keele St., Toronto, Ontario M3J 1P3 Canada.
authors.forename: Anna
authors.initials: A
authors.lastname: Vainshtein
authors.affiliation: Muscle Health Research Centre, School of Kinesiology and Health Science, York University, 4700 Keele St., Toronto, Ontario M3J 1P3 Canada.
authors.forename: Eric Ma
authors.initials: EM
authors.lastname: Desjardins
authors.affiliation: Department of Biomedical Sciences, University of Padova, Viale G. Colombo 3, I-35121 Padova, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Armani
authors.affiliation: Department of Biomedical Sciences, University of Padova, Viale G. Colombo 3, I-35121 Padova, Italy ; Venetian Institute of Molecular Medicine, 35129 Padova, Italy ; Telethon Institute of Genetics and Medicine (TIGEM), 80131 Napoli, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Sandri
authors.affiliation: Muscle Health Research Centre, School of Kinesiology and Health Science, York University, 4700 Keele St., Toronto, Ontario M3J 1P3 Canada.
authors.forename: David A
authors.initials: DA
authors.lastname: Hood
keywords: Autophagy; Disuse; Mitochondria; Mitochondrial turnover; Mitophagy; Muscle atrophy; PGC-1α; TFEB
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