title: Lysosomal two-pore channel subtype 2 (TPC2) regulates skeletal muscle autophagic signaling.
abstract: Postnatal skeletal muscle mass is regulated by the balance between anabolic protein synthesis and catabolic protein degradation, and muscle atrophy occurs when protein homeostasis is disrupted. Autophagy has emerged as critical in clearing dysfunctional organelles and thus in regulating protein turnover. Here we show that endolysosomal two-pore channel subtype 2 (TPC2) contributes to autophagy signaling and protein homeostasis in skeletal muscle. Muscles derived from Tpcn2(-/-) mice exhibit an atrophic phenotype with exacerbated autophagy under starvation. Compared with wild types, animals lacking TPC2 demonstrated an enhanced autophagy flux characterized by increased accumulation of autophagosomes upon combined stress induction by starvation and colchicine treatment. In addition, deletion of TPC2 in muscle caused aberrant lysosomal pH homeostasis and reduced lysosomal protease activity. Association between mammalian target of rapamycin and TPC2 was detected in skeletal muscle, allowing for appropriate adjustments to cellular metabolic states and subsequent execution of autophagy. TPC2 therefore impacts mammalian target of rapamycin reactivation during the process of autophagy and contributes to maintenance of muscle homeostasis.
authors.affiliation: From the Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio 43210, pei-hui.lin@osumc.edu.
authors.forename: Pei-Hui
authors.initials: PH
authors.lastname: Lin
authors.affiliation: From the Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio 43210.
authors.forename: Pu
authors.initials: P
authors.lastname: Duann
authors.affiliation: Department of Anatomy, Saitama Medical University, Saitama 350-0495, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Komazaki
authors.affiliation: From the Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio 43210.
authors.forename: Ki Ho
authors.initials: KH
authors.lastname: Park
authors.affiliation: From the Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio 43210.
authors.forename: Haichang
authors.initials: H
authors.lastname: Li
authors.affiliation: From the Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio 43210.
authors.forename: Mingzhai
authors.initials: M
authors.lastname: Sun
authors.affiliation: From the Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio 43210.
authors.forename: Mathew
authors.initials: M
authors.lastname: Sermersheim
authors.affiliation: From the Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio 43210.
authors.forename: Kristyn
authors.initials: K
authors.lastname: Gumpper
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford OX1 3QT, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Parrington
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford OX1 3QT, United Kingdom.
authors.forename: Antony
authors.initials: A
authors.lastname: Galione
authors.affiliation: Centre for Integrative Physiology, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh EH8 9XD, Scotland, United Kingdom, and.
authors.forename: A Mark
authors.initials: AM
authors.lastname: Evans
authors.affiliation: Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center, Houston, Texas 77030.
authors.forename: Michael X
authors.initials: MX
authors.lastname: Zhu
authors.affiliation: From the Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio 43210, jianjie.ma@osumc.edu.
authors.forename: Jianjie
authors.initials: J
authors.lastname: Ma
mesh_terms: D000818:Animals; D001343:Autophagy; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D006863:Hydrogen-Ion Concentration; D008247:Lysosomes / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D010447:Peptide Hydrolases / Q000378:metabolism; D010588:Phagosomes / Q000378:metabolism / Q000648:ultrastructure; D015398:Signal Transduction; D013312:Stress, Physiological; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D015220:Calcium Channels; C546785:TPCN2 protein, mouse; D058570:TOR Serine-Threonine Kinases; D010447:Peptide Hydrolases
keywords: Autophagy; Calcium Channel; Lysosome; Muscle Atrophy; Protein Turnover