title: Defective autophagy and mTORC1 signaling in myotubularin null mice.
abstract: Autophagy is a vesicular trafficking pathway that regulates the degradation of aggregated proteins and damaged organelles. Initiation of autophagy requires several multiprotein signaling complexes, such as the ULK1 kinase complex and the Vps34 lipid kinase complex, which generates phosphatidylinositol 3-phosphate [PtdIns(3)P] on the forming autophagosomal membrane. Alterations in autophagy have been reported for various diseases, including myopathies. Here we show that skeletal muscle autophagy is compromised in mice deficient in the X-linked myotubular myopathy (XLMTM)-associated PtdIns(3)P phosphatase myotubularin (MTM1). Mtm1-deficient muscle displays several cellular abnormalities, including a profound increase in ubiquitin aggregates and abnormal mitochondria. Further, we show that Mtm1 deficiency is accompanied by activation of mTORC1 signaling, which persists even following starvation. In vivo pharmacological inhibition of mTOR is sufficient to normalize aberrant autophagy and improve muscle phenotypes in Mtm1 null mice. These results suggest that aberrant mTORC1 signaling and impaired autophagy are consequences of the loss of Mtm1 and may play a primary role in disease pathogenesis.
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Fetalvero
authors.forename: Yenyen
authors.initials: Y
authors.lastname: Yu
authors.forename: Margaret
authors.initials: M
authors.lastname: Goetschkes
authors.forename: Guiqing
authors.initials: G
authors.lastname: Liang
authors.forename: Reginald A
authors.initials: RA
authors.lastname: Valdez
authors.forename: Ty
authors.initials: T
authors.lastname: Gould
authors.forename: Ellen
authors.initials: E
authors.lastname: Triantafellow
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bergling
authors.forename: Joseph
authors.initials: J
authors.lastname: Loureiro
authors.forename: John
authors.initials: J
authors.lastname: Eash
authors.forename: Victor
authors.initials: V
authors.lastname: Lin
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Porter
authors.forename: Peter M
authors.initials: PM
authors.lastname: Finan
authors.forename: Kenneth
authors.initials: K
authors.lastname: Walsh
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Mao
authors.forename: Leon O
authors.initials: LO
authors.lastname: Murphy
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000235:genetics*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D046912:Multiprotein Complexes; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020914:Myopathies, Structural, Congenital / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D046912:Multiprotein Complexes; D018129:Phosphatidylinositol Phosphates; D011506:Proteins; D025801:Ubiquitin; C055525:phosphatidylinositol 3-phosphate; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C099588:myotubularin; D020123:Sirolimus