title: Muscle-specific Drp1 overexpression impairs skeletal muscle growth via translational attenuation.
abstract: Mitochondrial fission and fusion are essential processes in the maintenance of the skeletal muscle function. The contribution of these processes to muscle development has not been properly investigated in vivo because of the early lethality of the models generated so far. To define the role of mitochondrial fission in muscle development and repair, we have generated a transgenic mouse line that overexpresses the fission-inducing protein Drp1 specifically in skeletal muscle. These mice displayed a drastic impairment in postnatal muscle growth, with reorganisation of the mitochondrial network and reduction of mtDNA quantity, without the deficiency of mitochondrial bioenergetics. Importantly we found that Drp1 overexpression activates the stress-induced PKR/eIF2α/Fgf21 pathway thus leading to an attenuated protein synthesis and downregulation of the growth hormone pathway. These results reveal for the first time how mitochondrial network dynamics influence muscle growth and shed light on aspects of muscle physiology relevant in human muscle pathologies.
authors.affiliation: E. Medea Scientific Institute, Bosisio, Parini, Italy.
authors.forename: T
authors.initials: T
authors.lastname: Touvier
authors.affiliation: Department of Clinical and Biomedical Sciences, Consiglio Nazionale delle Ricerche Institute of Neuroscience, L. Sacco University Hospital, Università di Milano, Milan, Italy.
authors.forename: C
authors.initials: C
authors.lastname: De Palma
authors.affiliation: Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Rigamonti
authors.affiliation: 1] Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milan, Italy [2] Department of Health Sciences, University of Milano-Bicocca, Monza, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Scagliola
authors.affiliation: 1] Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milan, Italy [2] Department of Health Sciences, University of Milano-Bicocca, Monza, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Incerti
authors.affiliation: Laboratoire de Biologie Moléculaire de la Cellule, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5239, IFR128, Université de Lyon, Equipe Différenciation Neuromusculaire, Ecole Normale Supérieure, Lyon Cedex 07, France.
authors.forename: L
authors.initials: L
authors.lastname: Mazelin
authors.affiliation: Laboratoire de Biologie Moléculaire de la Cellule, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5239, IFR128, Université de Lyon, Equipe Différenciation Neuromusculaire, Ecole Normale Supérieure, Lyon Cedex 07, France.
authors.forename: J-L
authors.initials: JL
authors.lastname: Thomas
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: D'Antonio
authors.affiliation: Neuroradiology Group, Imaging Core, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Politi
authors.affiliation: Laboratoire de Biologie Moléculaire de la Cellule, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5239, IFR128, Université de Lyon, Equipe Différenciation Neuromusculaire, Ecole Normale Supérieure, Lyon Cedex 07, France.
authors.forename: L
authors.initials: L
authors.lastname: Schaeffer
authors.affiliation: 1] E. Medea Scientific Institute, Bosisio, Parini, Italy [2] Department of Clinical and Biomedical Sciences, Consiglio Nazionale delle Ricerche Institute of Neuroscience, L. Sacco University Hospital, Università di Milano, Milan, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Clementi
authors.affiliation: 1] Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milan, Italy [2] Department of Health Sciences, University of Milano-Bicocca, Monza, Italy.
authors.forename: S
authors.identifier: 0000000317535346
authors.initials: S
authors.lastname: Brunelli
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004272:DNA, Mitochondrial / Q000378:metabolism; D034281:Dynamins / Q000235:genetics / Q000378:metabolism*; D047468:Immunoprecipitation; D053078:Membrane Potential, Mitochondrial / Q000235:genetics / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism*; D010101:Oxygen Consumption / Q000502:physiology
chemical_list: D004272:DNA, Mitochondrial; C486391:Dnm1l protein, mouse; D034281:Dynamins