The Role of Glycogen Synthase Kinase 3 Activity in the Regulation of Mitochondrial Biogenesis in Rat Postural Muscle under Hindlimb Unloading

Mechanical unloading of skeletal muscles is observed under microgravity in astronauts, and in terrestrial conditions with bed rest, immobilization of limbs, and various musculoskeletal disorders. It is characterized by the complete or partial elimination of the support afferentation, which leads to the disappearance or a significant decrease in the contractile activity of the postural soleus muscle, and subsequent skeletal muscle remodeling, such as atrophy of muscle fibers, a decrease in the level of mitochondrial biogenesis, transformation of the myosin phenotype resulting in increased muscle fatigue (muscle weakness). Glycogen synthase kinase 3 (GSK-3) can regulate both the expression of the slow isoform of myosin heavy chains, and the expression of PGC1α, a key factor of mitochondrial biogenesis; based on these data, we assumed that pharmacological inhibition of GSK-3 during 7 days of hindlimb suspension (HS) of rats can prevent inactivation of mitochondrial biogenesis in the soleus muscles of experimental animals. The decrease in mRNA expression of PGC1α, a key factor of mitochondrial biogenesis, observed after 7 days of HS, was prevented in the group that received a GSK-3 inhibitor. A decrease in the expression of several regulators of mitochondrial biogenesis and functions (TFAM, mitofusin-1, mitofusin-2, NRF-1, and NRF-2α) and the content of mitochondrial DNA was also prevented. These changes in the group with the GSK-3 inhibition were accompanied by a partial prevention of a decrease in the mRNA of the myh7b gene, which indicated a possible co-regulation of the expression of myosin genes and mitochondrial biogenesis in the rat soleus muscle under functional unloading.