Signaling effects of alpha-ketoglutarate precursor administration in rat soleus muscle during 7-day mechanical unloading

In conditions of insufficient muscle activity (during functional unloading), a number of pathological processes are observed that lead to a deterioration in muscle function. Some of these processes are based on changes in gene expression, leading to the transformation of muscle fibers from the "slow" type, which is fatigue-resistant and has predominantly oxidative type of metabolism, to the "fast" type, which has glycolytic metabolism and is quickly fatigued. The mechanisms of changes in gene expression in muscle fibers under conditions of functional unloading have not been sufficiently studied. In particular, the role of methylation of CpG sequences in promoter regions of genes in the regulation of gene expression that mediate the “slow” or “fast” phenotype of muscle fibers has been virtually unexplored. We assume that a decrease in the expression of several genes regulating mitochondrial biogenesis and the phenotype of muscle fibers under conditions of muscle unloading can be determined by a deficiency of alpha-ketoglutarate (a coenzyme of TET translocases that demethylate CpG islands). To test this assumption, male Wistar rats were divided into three groups of 8 animals in each: (1) group C, vivarium control with daily intraperitoneal administration of placebo (saline); (2) group 7HS, 7-day hind limb suspension with daily intraperitoneal administration of placebo; (3) group 7HSD, 7-day hind limb suspension with daily intraperitoneal administration of 200 mg/kg dimethyl-2-ketoglutarate (alpha-ketoglutarate precursor). The analysis of the experimental data obtained has shown that administration of dimethyl-2-ketoglutarate to the hind limb suspended animals partially prevents the decline expression of mRNA regulators of mitochondrial biogenesis and mitochondrial DNA content. This effect may be mediated by the drug's effect on еру CpG methylation. However, in the 7HSD group there was also an upregulation of AMP-activated protein kinase phosphorylation levels compared to the 7HS and C groups, which may explain the effect of dimethyl-2-ketoglutarate on the expression of regulators of mitochondrial mRNA biogenesis and mitochondrial DNA content during rat hindlimb suspension.