Regulation of Skeletal Muscle Plasticity by Glycogen Synthase Kinase-3β: A Potential Target for the Treatment of Muscle Wasting

Koen J.P.      Verhees; Nicholas A.M.      Pansters; Annemie M.W.J.      Schols; Ramon C.J.      Langen

Abstract

Muscle wasting is a prevalent and disabling condition in chronic disease and cancer and has been associated with increased mortality and impaired efficacy of surgical and medical interventions. Pharmacological therapies to combat muscle wasting are currently limited but considered as an important unmet medical need. Muscle wasting has been attributed to increased muscle proteolysis, and in particular ubiquitin 26S-proteasome system (UPS)-dependent protein breakdown. However, rates of muscle protein synthesis are also subject to extensive (patho) physiological regulation, and the balance between synthesis and degradation ultimately determines net muscle protein turnover. As multinucleated muscle fibers accommodate threshold changes in muscle protein content by the accretion and loss of muscle nuclei, myonuclear turnover may additionally determine muscle mass. Current insights in the mechanisms dictating muscle mass plasticity not only reveal intricate interactions and crosstalk between these processes, but imply the existence of signaling molecules that act as molecular switchboards, which coordinate and integrate cellular responses upon conditions that evoke changes in muscle mass. These “master regulators” of skeletal muscle mass plasticity are preferred targets for pharmacological modulation of skeletal muscle wasting. In this review Glycogen synthase kinase-3β (GSK-3β) is highlighted as a master regulator of muscle mass plasticity since, in addition to its role in UPS-mediated muscle protein degradation, it also controls protein synthesis, and influences myonuclear accretion and cell death. Moreover, the regulation of GSK-3β activity as well as currently available pharmacological inhibitors are described and discussed in the context of multimodal treatment strategies aimed at the inhibition of GSK-3β, and optimal exploitation of its potential role as a central regulator of skeletal muscle mass plasticity for the treatment of muscle wasting.

Keywords: Muscle plasticity, Glycogen synthase kinase-3β, muscle atrophy, regeneration, signal transduction, ubiquitin 26S-proteasome system, proteolysis, protein synthesis.