The Role of GSK-3β in the Regulation of Protein Turnover, Myosin Phenotype, and Oxidative Capacity in Skeletal Muscle under Disuse Conditions.

Timur M Mirzoev,Boris S Shenkman,Kristina A Sharlo

doi:10.3390/ijms22105081

Abstract

Skeletal muscles, being one of the most abundant tissues in the body, are involved in many vital processes, such as locomotion, posture maintenance, respiration, glucose homeostasis, etc. Hence, the maintenance of skeletal muscle mass is crucial for overall health, prevention of various diseases, and contributes to an individual’s quality of life. Prolonged muscle inactivity/disuse (due to limb immobilization, mechanical ventilation, bedrest, spaceflight) represents one of the typical causes, leading to the loss of muscle mass and function. This disuse-induced muscle loss primarily results from repressed protein synthesis and increased proteolysis. Further, prolonged disuse results in slow-to-fast fiber-type transition, mitochondrial dysfunction and reduced oxidative capacity. Glycogen synthase kinase 3β (GSK-3β) is a key enzyme standing at the crossroads of various signaling pathways regulating a wide range of cellular processes. This review discusses various important roles of GSK-3β in the regulation of protein turnover, myosin phenotype, and oxidative capacity in skeletal muscles under disuse/unloading conditions and subsequent recovery. According to its vital functions, GSK-3β may represent a perspective therapeutic target in the treatment of muscle wasting induced by chronic disuse, aging, and a number of diseases.

Highlights

In line with the above studies, our laboratory has observed a significant increase in Glycogen synthase kinase 3β (GSK-3β) (Ser9) phosphorylation in rat soleus muscle on the third day of recovery from disuse atrophy [57,58]
Novel findings linking the activity of GSK-3β to the regulation of such vital processes as protein synthesis/ribosome biogenesis, breakdown of myofibrillar proteins, mitochondrial biogenesis and expression of slow myosin heavy chain (MyHC) have steadily emerged during the last 5–10 years in the field of skeletal muscle physiology
While many studies associate unloading/reloading-induced changes in GSK-3β with signaling pathways implicated in the regulation of myosin phenotype, protein turnover and oxidative capacity, still remain several unanswered questions

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations It is well-established that mechanical unloading/disuse results in a slow-to-fast fiber type transition and a significant reduction in the rate of muscle protein synthesis, increased proteolysis, and subsequent fiber atrophy (loss of muscle mass) [1,2,3]. We will focus on the effects of mechanical unloading and subsequent recovery on GSK-3β activity in a mammalian skeletal muscle as well as discuss recent advances concerning a potential role of this kinase in the regulation of protein synthesis and degradation, myosin phenotype, and oxidative capacity under disuse conditions. To our knowledge, there is a lack of reviews in the field dedicated to recent findings related to the role of GSK-3β in skeletal muscle metabolism during recovery from disuse atrophy

Regulation of GSK-3β Activity

The Role of GSK-3β in the Regulation of Protein Synthesis and Breakdown

Impact of Mechanical Unloading on GSK-3β Activity and Possible Roles of this

Findings

Conclusions and Perspectives