Lysosomal two-pore channel subtype 2 (TPC2) regulates skeletal muscle autophagic signaling.
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.
['Lin|Pei-Hui|PH|', 'Duann|Pu|P|', 'Komazaki|Shinji|S|', 'Park|Ki Ho|KH|', 'Li|Haichang|H|', 'Sun|Mingzhai|M|', 'Sermersheim|Mathew|M|', 'Gumpper|Kristyn|K|', 'Parrington|John|J|', 'Galione|Antony|A|', 'Evans|A Mark|AM|', 'Zhu|Michael X|MX|', 'Ma|Jianjie|J|']
D000818:Animals D001343:Autophagy D015220:Calcium Channels D006706:Homeostasis D006863:Hydrogen-Ion Concentration D008247:Lysosomes D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D018482:Muscle, Skeletal D010447:Peptide Hydrolases D010588:Phagosomes D015398:Signal Transduction D013312:Stress, Physiological D058570:TOR Serine-Threonine Kinases
Lysosome Muscle Atrophy Autophagy Protein Turnover Calcium Channel