title: Autophagic flux and oxidative capacity of skeletal muscles during acute starvation.
abstract: Autophagy is an important proteolytic pathway in skeletal muscles. The roles of muscle fiber type composition and oxidative capacity remain unknown in relation to autophagy. The diaphragm (DIA) is a fast-twitch muscle fiber with high oxidative capacity, the tibialis anterior (TA) muscle is a fast-twitch muscle fiber with low oxidative capacity, and the soleus muscle (SOL) is a slow-twitch muscle with high oxidative capacity. We hypothesized that oxidative capacity is a major determinant of autophagy in skeletal muscles. Following acute (24 h) starvation of adult C57/Bl6 mice, each muscle was assessed for autophagy and compared with controls. Autophagy was measured by monitoring autophagic flux following leupeptin (20 mg/kg) or colchicine (0.4 mg/kg/day) injection. Oxidative capacity was measured by monitoring citrate synthase activity. In control mice, autophagic flux values were significantly greater in the TA than in the DIA and SOL. In acutely starved mice, autophagic flux increased, most markedly in the TA, and several key autophagy-related genes were significantly induced. In both control and starved mice, there was a negative linear correlation of autophagic flux with citrate synthase activity. Starvation significantly induced AMPK phosphorylation and inhibited AKT and RPS6KB1 phosphorylation, again most markedly in the TA. Starvation induced Foxo1, Foxo3, and Foxo4 expression and attenuated the phosphorylation of their gene products. We conclude that both basal and starvation-induced autophagic flux are greater in skeletal muscles with low oxidative capacity as compared with those with high oxidative capacity and that this difference is mediated through selective activation of the AMPK pathway and inhibition of the AKT-MTOR pathways.
authors: Department of Critical Care Medicine; McGill University Health Centre and Meakins-Christie Laboratories; Department of Medicine; McGill University; Montréal, Québec, Canada.
authors: Mahroo
authors: M
authors: Mofarrahi
authors: Department of Critical Care Medicine; McGill University Health Centre and Meakins-Christie Laboratories; Department of Medicine; McGill University; Montréal, Québec, Canada.
authors: Yeting
authors: Y
authors: Guo
authors: Division of Pulmonary and Critical Care Medicine; Department of Medicine; Brigham and Women's Hospital; Boston, MA USA.
authors: Jeffrey A
authors: JA
authors: Haspel
authors: Division of Pulmonary and Critical Care Medicine; Department of Medicine; Brigham and Women's Hospital; Boston, MA USA.
authors: Augustine M K
authors: AM
authors: Choi
authors: Department of Anatomy and Cell Biology; McGill University; Montréal, Québec, Canada.
authors: Elaine C
authors: EC
authors: Davis
authors: Department of Critical Care Medicine; McGill University Health Centre and Meakins-Christie Laboratories; Department of Medicine; McGill University; Montréal, Québec, Canada.
authors: Gilles
authors: G
authors: Gouspillou
authors: Department of Critical Care Medicine; McGill University Health Centre and Meakins-Christie Laboratories; Department of Medicine; McGill University; Montréal, Québec, Canada.
authors: Russell T
authors: RT
authors: Hepple
authors: Faculty of Pharmacy; Université de Montréal; Montréal, Québec, Canada.
authors: Richard
authors: R
authors: Godin
authors: Faculty of Pharmacy; Université de Montréal; Montréal, Québec, Canada.
authors: Yan
authors: Y
authors: Burelle
authors: Department of Critical Care Medicine; McGill University Health Centre and Meakins-Christie Laboratories; Department of Medicine; McGill University; Montréal, Québec, Canada.
authors: Sabah N A
authors: SN
authors: Hussain
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D008297:Male; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D018656:Muscle Fibers, Fast-Twitch / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D010084:Oxidation-Reduction; D010766:Phosphorylation; D015398:Signal Transduction / Q000502:physiology; D013217:Starvation / Q000378:metabolism*
keywords: autophagy; fiber-type composition; oxidative capacity; skeletal muscles; starvation