title: Myopathy caused by mammalian target of rapamycin complex 1 (mTORC1) inactivation is not reversed by restoring mitochondrial function.
abstract: Mammalian target of rapamycin complex 1 (mTORC1) is central to the control of cell, organ, and body size. Skeletal muscle-specific inactivation of mTORC1 in mice results in smaller muscle fibers, fewer mitochondria, increased glycogen stores, and a progressive myopathy that causes premature death. In mTORC1-deficient muscles, peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α), which regulates mitochondrial biogenesis and glucose homeostasis, is strongly down-regulated. Here we tested whether induction of mitochondrial biogenesis pharmacologically or by the overexpression of PGC-1α is sufficient to reverse the phenotype of mice deficient for mTORC1. We show that both approaches normalize mitochondrial function, such as oxidative capacity and expression of mitochondrial genes. However, they do not prevent or delay the progressive myopathy. In addition, we find that mTORC1 has a much stronger effect than PGC-1α on the glycogen content in muscle. This effect is based on the strong activation of PKB/Akt in mTORC1-deficient mice. We also show that activation of PKB/Akt not only affects glycogen synthesis but also diminishes glycogen degradation. Thus, our work provides strong functional evidence that mitochondrial dysfunction in mice with inactivated mTORC1 signaling is caused by the down-regulation of PGC-1α. However, our data also show that the impairment of mitochondria does not lead directly to the lethal myopathy.
authors.affiliation: Biozentrum,  University of Basel, 4056 Basel,  Switzerland.
authors.forename: Klaas
authors.initials: K
authors.lastname: Romanino
authors.forename: Laetitia
authors.initials: L
authors.lastname: Mazelin
authors.forename: Verena
authors.initials: V
authors.lastname: Albert
authors.forename: Agnès
authors.initials: A
authors.lastname: Conjard-Duplany
authors.forename: Shuo
authors.initials: S
authors.lastname: Lin
authors.forename: C Florian
authors.initials: CF
authors.lastname: Bentzinger
authors.forename: Christoph
authors.initials: C
authors.lastname: Handschin
authors.forename: Pere
authors.initials: P
authors.lastname: Puigserver
authors.forename: Francesco
authors.initials: F
authors.lastname: Zorzato
authors.forename: Laurent
authors.initials: L
authors.lastname: Schaeffer
authors.forename: Yann-Gaël
authors.initials: YG
authors.lastname: Gangloff
authors.forename: Markus A
authors.initials: MA
authors.lastname: Rüegg
mesh_terms: D000818:Animals; D001629:Bezafibrate / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006003:Glycogen / Q000737:chemistry / Q000378:metabolism; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D008931:Mitochondria, Muscle / Q000378:metabolism; D008957:Models, Genetic; D046912:Multiprotein Complexes; D018482:Muscle, Skeletal / Q000378:metabolism; D009135:Muscular Diseases / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011506:Proteins / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors
chemical_list: D046912:Multiprotein Complexes; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D011506:Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D006003:Glycogen; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D001629:Bezafibrate