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

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.

GSK3 inhibition improves skeletal muscle function and whole-body metabolism in the severe DBA/2Jmdxmouse model

“…Consistent with its role as a negative regulator of muscle size 10 , we found that GSK3 inhibition with tideglusib treatment restored EDL:body mass ratio in D2 mdx mice to levels comparable with WT mice (Fig. 2a).…”

“…It is well-established that GSK3 counteracts calcineurin by rephosphorylating NFAT, thereby preventing its nuclear activation and the transcription of its downstream targets 10 . Thus, in addition to its role in regulating muscle mass, we and others have shown that GSK3 negatively regulates the oxidative fiber type, and that its inhibition in muscle can promote the oxidative myogenic program 10,25,42 . Our findings presented here are strongly aligned with this, as we observed a significant increase in the proportion of oxidative (I and IIA) fibers in tideglusib treated vs vehicle treated D2 mdx EDL muscles.…”

“…Importantly, the inhibition of GSK3 has been viewed as a viable therapeutic strategy for many diseases and conditions including, but not limited to, Alzheimer’s disease, Parkinson’s disease, and diabetes 9 . In the context of muscle, GSK3 is a known negative regulator of muscle mass that specifically suppresses protein synthesis and myoblast fusion while also promoting proteolytic degradation (for review see ref 10 ). In fact, GSK3 been implicated in other muscle wasting diseases such as myotonic dystrophy type 1 (DM1) and limb girdle muscular dystrophy, with its inhibition leading to disease attenuation and enhanced muscle performance 11,12 .…”

Effects of Various Muscle Disuse States and Countermeasures on Muscle Molecular Signaling

“…The use of GSK-3β kinase inhibitors during hindlimb unloading in rats led to the prevention of a decrease in the expression of PGC-1α and mitochondrial proteins and the prevention of the slow-to-fast fiber-type transformation [ 201 , 231 ]. In recent years, GSK-3β was shown to play a significant role in the development of changes in postural muscles during variants of muscle unloading; the inhibition of GSK-3 can lead to an increase in the work capacity of skeletal muscles in rodents, which makes GSK-3β inhibitors some of the most promising pharmacological agents as a countermeasure against unloading-induced changes [ 280 , 281 ].…”

The Role of Glycogen Synthase Kinase-3 in the Regulation of Ribosome Biogenesis in Rat Soleus Muscle under Disuse Conditions

“…Glycogen synthase kinase 3 (GSK-3) is a multifaceted Ser/Thr protein kinase known to phosphorylate several hundred substrates [ 25 ], thereby regulating a wide range of intracellular processes including protein turnover in skeletal muscle [ 26 ]. GSK-3 exists in two isoforms, GSK-3α and GSK-3β, among which GSK-3β is considered to be the most expressed and active isoform within skeletal muscles [ 27 ].…”