Inactivation of glycogen synthase kinase-3 is not required for recovery of muscle mass of disuse-atrophied muscle

Abstract

Muscle wasting impairs exercise capacity in COPD. Improved understanding of the molecular mechanisms governing muscle mass during wasting and recovery will benefit the development of improved intervention strategies. The insulin-like growth factor (IGF)-I signaling pathway is involved in muscle mass regulation, and we previously observed glycogen synthase kinase 3 (GSK-3) inhibition by IGF-I signaling during muscle mass recovery. We hypothesized that inactivation of GSK-3 is required for recovery of disuse-atrophied skeletal muscle. Wild-type mice and S9/21A-GSK-3alpha/beta knock-in (GSK-3-KI, inactivation-resistant) mice were subjected to a hind-limb suspension model of reversible disuse-induced muscle atrophy, and followed during recovery. Indices of muscle mass, protein synthesis and proteolysis, and post-natal myogenesis, were monitored during reloading of atrophied muscle. No differences in muscle mass recovery were observed between control and KI-mice. Reloading supressed the mRNA levels of effectors of proteolysis (Atrogin-1, MuRF1, Bnip3) equally in WT and GSK-3-KI mice. Protein synthesis signalling was equally induced by reloading of atrophied muscle in WT and KI mice, as evidenced by increased phosphorylation levels of Akt, GSK-3beta (WT only), mTOR, 4E-BP1, S6K1. Satellite cell activation, proliferation, and differentiation revealed a transient induction during reloading, which except for attenuated myogenin expression in KI mice, was similar in WT and KI mice. Combined, these data indicate that GSK-3 inactivation is not required for recovery of muscle mass of disuse-atrophied muscle. This work was supported by the Dutch Lung Foundation (3.2.07.017).