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 both in microgravity conditions during space flight and on Earth during bed rest, immobilization, and neurological disorders. This condition is characterized by a complete or partial elimination of support afferentation, which leads to the disappearance or significant decrease in the contractile activity of the postural soleus muscle and subsequent skeletal muscle remodeling resulting in muscle fiber atrophy, a decrease in the level of mitochondrial biogenesis, transformation of the myosin phenotype, and increased muscle fatigue (muscle weakness). Glycogen synthase kinase 3 (GSK-3) is able to regulate both the expression of the slow isoform of myosin heavy chains and the expression of the key factor of mitochondrial biogenesis PGCl alpha. On the basis of these data we suggested that pharmacological inhibition of GSK-3 during 7 days of rat hindlimb unloading (hindlimb suspension) can prevent the inactivation of mitochondrial biogenesis in soleus muscles of experimental animals. A decrease in mRNA expression of the key mitochondrial biogenesis factor PGCl alpha, observed after 7 days of unloading, was prevented in the unloading group treated with the GSK-3 inhibitor. The unloading -induced decrease in the expression of a number of regulators of mitochondrial biogenesis (TFAM, mitofusins-1 and -2, NRF-1 and NRF-2 alpha) and the content of mitochondrial DNA was also prevented by the GSK-3 inhibitor. The observed changes in the hindlimb unloading + GSK-3 inhibitor group were accompanied by a partial prevention of the unloading related decrease in myh 7b gene mRNA indicating the possibility of co-regulation of slow myosin gene expression and mitochondrial biogenesis in rat soleus muscle under conditions of mechanical unloading.