Lysosomal two-pore channel subtype 2 (TPC2) regulates skeletal muscle autophagic signaling

Pei-Hui Lin, Pu Duann, Shinji Komazaki, Ki Ho Park, Haichang Li, Mingzhai Sun, Mathew Sermersheim, Kristyn Gumpper, John Parrington, Antony Galione, A Mark Evans, Michael X Zhu, Jianjie Ma

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)3377-89
Number of pages13
JournalJournal of Biological Chemistry
Volume290
Issue number6
DOIs
Publication statusPublished - 6 Feb 2015

Keywords

  • Animals
  • Autophagy
  • Calcium Channels
  • Homeostasis
  • Hydrogen-Ion Concentration
  • Lysosomes
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Muscle, Skeletal
  • Peptide Hydrolases
  • Phagosomes
  • Signal Transduction
  • Stress, Physiological
  • TOR Serine-Threonine Kinases

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