Skeletal muscle atrophy commonly occurs in acute and chronic disease. The expression of the muscle-specific E3 ligases atrogin-1 (MAFbx) and muscle RING finger 1 (MuRF1) is induced by atrophy stimuli such as glucocorticoids or absence of IGF-I/insulin and subsequent Akt signaling. We investigated whether glycogen synthase kinase-3β (GSK-3β), a downstream molecule in IGF-I/Akt signaling, is required for basal and atrophy stimulus-induced expression of atrogin-1 and MuRF1, and myofibrillar protein loss in C(2)C(12) skeletal myotubes. Abrogation of basal IGF-I signaling, using LY294002, resulted in a prominent induction of atrogin-1 and MuRF1 mRNA and was accompanied by a loss of myosin heavy chain fast (MyHC-f) and myosin light chains 1 (MyLC-1) and -3 (MyLC-3). The synthetic glucocorticoid dexamethasone (Dex) also induced the expression of both atrogenes and likewise resulted in the loss of myosin protein abundance. Genetic ablation of GSK-3β using small interfering RNA resulted in specific sparing of MyHC-f, MyLC-1, and MyLC-3 protein levels after Dex treatment or impaired IGF-I/Akt signaling. Interestingly, loss of endogenous GSK-3β suppressed both basal and atrophy stimulus-induced atrogin-1 and MuRF1 expression, whereas pharmacological GSK-3β inhibition, using CHIR99021 or LiCl, only reduced atrogin-1 mRNA levels in response to LY294002 or Dex. In conclusion, our data reveal that myotube atrophy and myofibrillar protein loss are GSK-3β dependent, and demonstrate for the first time that basal and atrophy stimulus-induced atrogin-1 mRNA expression requires GSK-3β enzymatic activity, whereas MuRF1 expression depends solely on the physical presence of GSK-3β.

Muscle wasting impairs physical performance, increases mortality and reduces medical intervention efficacy in chronic diseases and cancer. Developing proficient intervention strategies requires improved understanding of the molecular mechanisms governing muscle mass wasting and recovery. Involvement of muscle protein- and myonuclear turnover during recovery from muscle atrophy has received limited attention. The insulin-like growth factor (IGF)-I signaling pathway has been implicated in muscle mass regulation. As glycogen synthase kinase 3 (GSK-3) is inhibited by IGF-I signaling, we hypothesized that muscle-specific GSK-3β deletion facilitates the recovery of disuse-atrophied skeletal muscle. Wild-type mice and mice lacking muscle GSK-3β (MGSK-3β KO) were subjected to a hindlimb suspension model of reversible disuse-induced muscle atrophy and followed during recovery. Indices of muscle mass, protein synthesis and proteolysis, and post-natal myogenesis which contribute to myonuclear accretion, were monitored during the reloading of atrophied muscle. Early muscle mass recovery occurred more rapidly in MGSK-3β KO muscle. Reloading-associated changes in muscle protein turnover were not affected by GSK-3β ablation. However, coherent effects were observed in the extent and kinetics of satellite cell activation, proliferation and myogenic differentiation observed during reloading, suggestive of increased myonuclear accretion in regenerating skeletal muscle lacking GSK-3β. This study demonstrates that muscle mass recovery and post-natal myogenesis from disuse-atrophy are accelerated in the absence of GSK-3β.

Cardiac device infections in France are associated with substantial costs, when considering inpatient hospitalizations. Strategies to minimize the rate of CIED infection should be a priority for health care providers and payers.

A shift in quadriceps muscle metabolic profile toward decreased oxidative metabolism and increased glycolysis is a consistent finding in chronic obstructive pulmonary disease (COPD). Chronic inflammation has been proposed as a trigger of this pathological metabolic adaptation. Indeed, the proinflammatory cytokine TNF-α impairs muscle oxidative metabolism through activation of the nuclear factor-κB (NF-κB) pathway. Putative effects on muscle glycolysis, however, are unclear. We hypothesized that TNF-α-induced NF-κB signaling stimulates muscle glycolytic metabolism through activation of the glycolytic regulator hypoxia-inducible factor-1α (HIF-1α). Wild-type C2C12 and C2C12-IκBα-SR (blocked NF-κB signaling) myotubes were stimulated with TNF-α, and its effects on glycolytic metabolism and involvement of the HIF pathway herein were investigated. As proof of principle, expression of HIF signaling constituents was investigated in quadriceps muscle biopsies of a previously well-characterized cohort of clinically stable patients with severe COPD and healthy matched controls. TNF-α increased myotube glucose uptake and lactate production and enhanced the activity and expression levels of multiple effectors of muscle glycolytic metabolism in a NF-κB-dependent manner. In addition, TNF-α activated HIF signaling, which required classical NF-κB activation. Moreover, the knockdown of HIF-1α largely attenuated TNF-α-induced increases in glycolytic metabolism. Accordingly, the mRNA levels of HIF-1α and the HIF-1α target gene, vascular endothelial growth factor (VEGF), were increased in muscle biopsies of COPD patients compared with controls, which was most pronounced in the patients with high levels of muscle TNF-α. In conclusion, these data show that TNF-α-induced classical NF-κB activation enhances muscle glycolytic metabolism in a HIF-1α-dependent manner.