Muscle-specific GSK-3β ablation accelerates regeneration of disuse-atrophied skeletal muscle

Abstract

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.

Differential regulation of muscle protein turnover in response to emphysema and acute pulmonary inflammation

“…Although this does not affect muscle mass in emphysematous mice in the timeframe assessed here, this may ultimately culminate in muscle atrophy when sustained for longer periods or as a consequence of an impaired capacity to recover from loss of muscle mass [39]. …”

Angiotensin-II-induced Muscle Wasting is Mediated by 25-Hydroxycholesterol via GSK3β Signaling Pathway

“…However, in pathological conditions where IGF-1/Akt signaling is impaired, GSK3β is dephosphorylated at Ser9 and induces muscle loss via up-regulation of atrogin-1, MuRF1 and activation of the ubiquitin-proteasome pathway (Pansters et al, 2015). Activation of GSK-3β is implicated in various forms of muscle wasting including disuse (Pansters et al, 2015) and burn induced muscle loss (Fang et al, 2007). Muscle-specific GSK-3β deletion promotes the recovery of disuse-induced atrophy (Pansters et al, 2015).…”

“…Activation of GSK-3β is implicated in various forms of muscle wasting including disuse (Pansters et al, 2015) and burn induced muscle loss (Fang et al, 2007). Muscle-specific GSK-3β deletion promotes the recovery of disuse-induced atrophy (Pansters et al, 2015). Pharmacological inhibition of GSK-3β prevents TNF-α induced muscle loss in a guinea pig model of pulmonary inflammation associated muscle atrophy (Verhees et al, 2013).…”

Skeletal muscle unloading results in increased mitophagy and decreased mitochondrial biogenesis regulation

“…Twelve‐week‐old, young adult mice were divided in three groups, and subjected to no experimental procedure (baseline [BL]; n = 8), 3 days of muscle UL by hind limb suspension (HLS; n = 9), or 3 days of paired feeding (PF; n = 9). The HLS protocol was performed as previously described with the exception that isoflurane (Abbott, Abbott Park, IL) was used as an anesthetic. In short, the tail of the animals was wrapped in a tail suspension device and connected to a swivel hook to allow circular motility.…”