title: Calpain-dependent regulation of the skeletal muscle atrophy following unloading.
abstract: Unloading causes rapid skeletal muscle atrophy due to increased protein degradation via activation of calpains and decreased protein synthesis. Our study elucidated role of calpain-1 in the regulation of ubiquitin proteasome pathway (UPP) and anabolic processes mediated by Akt-mTOR-p70S6K and MAPK-Erk (p90RSK) signaling. We hypothesized that blocking calpain will inhibit activation of UPP and decrease protein degradation resulting in reduction of unloading-induced skeletal muscle atrophy. Rats were divided into three groups: non-treated control (C), three day hindlimb suspension with (HSPD) or without (HS) treatment with calpain inhibitor PD150606. When compared with control PD150606 treatment during unloading: 1) attenuated loss of muscle mass, 2) prevented accumulation of calpain-1 (1.8-fold in HS vs 1.3-fold in HSPD) and ubiquitin (2.3-fold in HS vs 0.7-fold in HSPD) mRNA and ubiquitinated proteins (1.6-fold in HS vs 0.8-fold in HSPD), 3) prevented decrease in the pAkt (0.4-fold in HS vs 1-fold in HSPD) and pFOXO3 (0.2-fold in HS vs 1.2-fold in HSPD) levels, 4) prevented increase in MAFbx (3.8-fold in HS vs 1.3-fold in HSPD) and eEF2k (1.8-fold in HS vs 0.6-fold in HSPD) mRNA. Our study indicates that blocking of calpain during unloading decreases skeletal muscle atrophy by inhibiting UPP activation and preserving anabolic signaling.
authors: Institute of Biomedical Problems, RAS, Moscow, Russia.
authors: Boris S
authors: BS
authors: Shenkman
authors: Institute of Biomedical Problems, RAS, Moscow, Russia.
authors: Svetlana P
authors: SP
authors: Belova
authors: Institute of Biomedical Problems, RAS, Moscow, Russia.
authors: Yulia N
authors: YN
authors: Lomonosova
authors: Department of Anatomy and Cell Biology, Indiana University School of Medicine-Northwest, Gary, IN, USA.
authors: Tatiana Y
authors: TY
authors: Kostrominova
authors: Institute of Biomedical Problems, RAS, Moscow, Russia; Faculty of Basic Medicine, Lomonosov Moscow State University, Moscow, Russia. Electronic address: nemirovskaya@bk.ru.
authors: Tatyana L
authors: TL
authors: Nemirovskaya
mesh_terms: D000179:Acrylates / Q000494:pharmacology*; D000818:Animals; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007103:Immobilization; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D009124:Muscle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009133:Muscular Atrophy / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D059748:Proteolysis / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000179:Acrylates; D009124:Muscle Proteins; C100442:PD 150606; D002154:Calpain
keywords: Calpain; MAFbx; Skeletal muscle unloading; Ubiquitin proteasome pathway; pFOXO3