title: PGC1-α over-expression prevents metabolic alterations and soleus muscle atrophy in hindlimb unloaded mice.
abstract: Prolonged skeletal muscle inactivity causes muscle fibre atrophy. Redox imbalance has been considered one of the major triggers of skeletal muscle disuse atrophy, but whether redox imbalance is actually the major cause or simply a consequence of muscle disuse remains of debate. Here we hypothesized that a metabolic stress mediated by PGC-1α down-regulation plays a major role in disuse atrophy. First we studied the adaptations of soleus to mice hindlimb unloading (HU) in the early phase of disuse (3 and 7 days of HU) with and without antioxidant treatment (trolox). HU caused a reduction in cross-sectional area, redox status alteration (NRF2, SOD1 and catalase up-regulation), and induction of the ubiquitin proteasome system (MuRF-1 and atrogin-1 mRNA up-regulation) and autophagy (Beclin1 and p62 mRNA up-regulation). Trolox completely prevented the induction of NRF2, SOD1 and catalase mRNAs, but not atrophy or induction of catabolic systems in unloaded muscles, suggesting that oxidative stress is not a major cause of disuse atrophy. HU mice showed a marked alteration of oxidative metabolism. PGC-1α and mitochondrial complexes were down-regulated and DRP1 was up-regulated. To define the link between mitochondrial dysfunction and disuse muscle atrophy we unloaded mice overexpressing PGC-1α. Transgenic PGC-1α animals did not show metabolic alteration during unloading, preserving muscle size through the reduction of autophagy and proteasome degradation. Our results indicate that mitochondrial dysfunction plays a major role in disuse atrophy and that compounds inducing PGC-1α expression could be useful to treat/prevent muscle atrophy.
authors.affiliation: Department of Molecular Medicine, University of Pavia, 27100, Pavia, Italy.
authors.forename: Jessica
authors.initials: J
authors.lastname: Cannavino
authors.affiliation: Department of Molecular Medicine, University of Pavia, 27100, Pavia, Italy.
authors.forename: Lorenza
authors.initials: L
authors.lastname: Brocca
authors.affiliation: Venetian Institute of Molecular Medicine and Dulbecco Telethon Institute, 35129, Padova, Italy Interuniversity Institute of Myology, University of Pavia, Pavia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Sandri
authors.affiliation: Department of Molecular Medicine, University of Pavia, 27100, Pavia, Italy Fondazione Salvatore Maugeri (IRCCS), Scientific Institute of Pavia, Pavia, Italy Interdipartimental Centre for Biology and Sport Medicine, University of Pavia, Pavia, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Bottinelli
authors.affiliation: Department of Molecular Medicine, University of Pavia, 27100, Pavia, Italy Interuniversity Institute of Myology, University of Pavia, Pavia, Italy Interdipartimental Centre for Biology and Sport Medicine, University of Pavia, Pavia, Italy map@unipv.it.
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Pellegrino
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001343:Autophagy; D000071186:Beclin-1; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D002839:Chromans / Q000494:pharmacology / Q000627:therapeutic use; D034281:Dynamins / Q000235:genetics / Q000378:metabolism; D019417:Hindlimb Suspension / Q000009:adverse effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009133:Muscular Atrophy / Q000378:metabolism* / Q000517:prevention & control; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000975:Antioxidants; D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D002839:Chromans; D009124:Muscle Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D012333:RNA, Messenger; D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; D002374:Catalase; C000606291:Sod1 protein, mouse; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C486692:Fbxo32 protein, rat; D044843:SKP Cullin F-Box Protein Ligases; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases; C486391:Dnm1l protein, mouse; D034281:Dynamins; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid