Recovery of muscle mass and muscle oxidative phenotype following disuse does not require GSK-3 inactivation

Background: Physical inactivity contributes to muscle wasting and reductions in mitochondrial oxidative phenotype (OXPHEN), reducing physical performance and quality of life during aging and in chronic disease. Previously, it was shown that inactivation of glycogen synthase kinase (GSK)-3 beta stimulates muscle protein accretion, myogenesis, and mitochondrial biogenesis. Additionally, GSK-3 beta is inactivated during recovery of disuse-induced muscle atrophy. Aim: Therefore, we hypothesize that GSK-3 inhibition is required for reloading-induced recovery of skeletal muscle mass and OXPHEN. Methods: Wild-type (WT) and whole-body constitutively active (C.A.) Ser(21/9) GSK-3 alpha/beta knock-in mice were subjected to a 14-day hind-limb suspension/14-day reloading protocol. Soleus muscle mass, fiber cross-sectional area (CSA), OXPHEN (abundance of sub-units of oxidative phosphorylation (OXPHOS) complexes and fiber-type composition), as well as expression levels of their main regulators (respectively protein synthesis/degradation, myogenesis and peroxisome proliferator-activated receptor-gamma co-activator-1 alpha (PGC-1 alpha) signaling) were monitored. Results: Subtle but consistent differences suggesting suppression of protein turnover signaling and decreased expression of several OXPHOS sub-units and PGC-1 alpha signaling constituents were observed at baseline in C.A. GSK-3 versus WT mice. Although soleus mass recovery during reloading occurred more rapidly in C.A. GSK-3 mice, this was not accompanied by a parallel increased CSA. The OXPHEN response to reloading was not distinct between C.A. GSK-3 and WT mice. No consistent or significant differences in reloading-induced changes in the regulatory steps of protein turnover, myogenesis or muscle OXPHEN were observed in C.A. GSK-3 compared to WT muscle. Conclusion: This study indicates that GSK-3 inactivation is dispensable for reloading-induced recovery of muscle mass and OXPHEN.