title: Suppression of mTORC1 activation in acid-α-glucosidase-deficient cells and mice is ameliorated by leucine supplementation.
abstract: Pompe disease is due to a deficiency in acid-α-glucosidase (GAA) and results in debilitating skeletal muscle wasting, characterized by the accumulation of glycogen and autophagic vesicles. Given the role of lysosomes as a platform for mTORC1 activation, we examined mTORC1 activity in models of Pompe disease. GAA-knockdown C2C12 myoblasts and GAA-deficient human skin fibroblasts of infantile Pompe patients were found to have decreased mTORC1 activation. Treatment with the cell-permeable leucine analog L-leucyl-L-leucine methyl ester restored mTORC1 activation. In vivo, Pompe mice also displayed reduced basal and leucine-stimulated mTORC1 activation in skeletal muscle, whereas treatment with a combination of insulin and leucine normalized mTORC1 activation. Chronic leucine feeding restored basal and leucine-stimulated mTORC1 activation, while partially protecting Pompe mice from developing kyphosis and the decline in muscle mass. Leucine-treated Pompe mice showed increased spontaneous activity and running capacity, with reduced muscle protein breakdown and glycogen accumulation. Together, these data demonstrate that GAA deficiency results in reduced mTORC1 activation that is partly responsible for the skeletal muscle wasting phenotype. Moreover, mTORC1 stimulation by dietary leucine supplementation prevented some of the detrimental skeletal muscle dysfunction that occurs in the Pompe disease mouse model.
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York;
authors.forename: Adi
authors.initials: A
authors.lastname: Shemesh
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York;
authors.forename: Yichen
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, People's Republic of China;
authors.forename: Yingjuan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, People's Republic of China;
authors.forename: Gong-She
authors.initials: GS
authors.lastname: Yang
authors.affiliation: Program in Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada; and.
authors.forename: Danielle E
authors.initials: DE
authors.lastname: Johnson
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York;
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Backer
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York; Department of Medicine, Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Pessin
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York; Department of Medicine, Albert Einstein College of Medicine, Bronx, New York haihong.zong@einstein.yu.edu.
authors.forename: Haihong
authors.initials: H
authors.lastname: Zong
mesh_terms: D000818:Animals; D002460:Cell Line; D019587:Dietary Supplements; D004151:Dipeptides / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D006003:Glycogen / Q000378:metabolism; D006009:Glycogen Storage Disease Type II / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D007738:Kyphosis / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D008247:Lysosomes / Q000187:drug effects / Q000201:enzymology; D000076222:Mechanistic Target of Rapamycin Complex 1; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D046912:Multiprotein Complexes / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D009133:Muscular Atrophy / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D032446:Myoblasts / Q000187:drug effects / Q000201:enzymology; D034622:RNA Interference; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014162:Transfection; D000520:alpha-Glucosidases / Q000172:deficiency* / Q000235:genetics
chemical_list: D004151:Dipeptides; D007328:Insulin; D046912:Multiprotein Complexes; C045139:leucyl-leucine-methyl ester; D006003:Glycogen; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; C509951:GAA protein, human; D000520:alpha-Glucosidases
keywords: Pompe disease; leucine; lysosome; mTORC1; muscle; α-glucosidase