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Abstract <p>Under conditions of insufficient muscle activity (with their functional unloading), a number of pathological processes are observed, leading to deterioration of muscle functions. Some of these processes are based on changes in gene expression, which leads to the transformation of the phenotype of muscle fibers from “slow,” with a predominantly oxidative metabolism and resistant to fatigue, to “fast,” with a predominantly glycolytic metabolism and prone to fatigue. Based on the literature data, it can be assumed that CpG methylation of promoter regions of genes may be involved in regulating the expression of genes that implement the “slow” and “fast” phenotype of muscle fibers. A decrease in the expression of genes regulating mitochondrial biogenesis and muscle fiber phenotype under conditions of mechanical muscle unloading may be determined by a lack of alpha-ketoglutarate (a coenzyme of TET translocases demethylating CpG islands). To test this hypothesis, male Wistar rats were divided into three groups of 8 animals each: (1) C, vivarium control with daily intraperitoneal administration of placebo (saline solution); (2) 7HS, 7-day hind limb suspension with daily intraperitoneal administration of placebo (saline solution), and (3) 7HSD, 7-day hind limb suspension with daily intraperitoneal administration of 200 mg/kg dimethyl-2-ketoglutarate (precursor of alpha-ketoglutarate). Based on the analysis of experimental data, it was found that the administration of dimethyl-2-ketoglutarate to the suspended animals partially prevents the decrease in the accumulation of mRNA regulators of mitochondrial biogenesis and the content of mitochondrial DNA observed during 7-day hind limb suspension. This effect can be realized through the violation of the CpG methylation by the drug; however, in the 7HSD group, an increase in the phosphorylation of AMP-activated protein kinase was also found compared to the 7HS and C groups, which may explain the effect of dimethyl-2-ketoglutarate on the accumulation of mRNA regulators of mitochondrial biogenesis and the content of mitochondrial DNA upon suspension of the hindlimbs of rats.</p>

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Signaling Effects of alpha-Ketoglutarate Precursor Administration in Rat Soleus Muscle under 7-Day Mechanical Unloading

  • 期刊论文

  • 发表日期：

    2026年5月20日

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  • K. A. Sharlo,
  • D. A. Sidorenko,
  • R. O. Bokov,
  • G. V. Galkin,
  • I. D. Lvova,
  • A. A. Kulishenko,
  • B. S. Shenkman

摘要

Abstract

Under conditions of insufficient muscle activity (with their functional unloading), a number of pathological processes are observed, leading to deterioration of muscle functions. Some of these processes are based on changes in gene expression, which leads to the transformation of the phenotype of muscle fibers from “slow,” with a predominantly oxidative metabolism and resistant to fatigue, to “fast,” with a predominantly glycolytic metabolism and prone to fatigue. Based on the literature data, it can be assumed that CpG methylation of promoter regions of genes may be involved in regulating the expression of genes that implement the “slow” and “fast” phenotype of muscle fibers. A decrease in the expression of genes regulating mitochondrial biogenesis and muscle fiber phenotype under conditions of mechanical muscle unloading may be determined by a lack of alpha-ketoglutarate (a coenzyme of TET translocases demethylating CpG islands). To test this hypothesis, male Wistar rats were divided into three groups of 8 animals each: (1) C, vivarium control with daily intraperitoneal administration of placebo (saline solution); (2) 7HS, 7-day hind limb suspension with daily intraperitoneal administration of placebo (saline solution), and (3) 7HSD, 7-day hind limb suspension with daily intraperitoneal administration of 200 mg/kg dimethyl-2-ketoglutarate (precursor of alpha-ketoglutarate). Based on the analysis of experimental data, it was found that the administration of dimethyl-2-ketoglutarate to the suspended animals partially prevents the decrease in the accumulation of mRNA regulators of mitochondrial biogenesis and the content of mitochondrial DNA observed during 7-day hind limb suspension. This effect can be realized through the violation of the CpG methylation by the drug; however, in the 7HSD group, an increase in the phosphorylation of AMP-activated protein kinase was also found compared to the 7HS and C groups, which may explain the effect of dimethyl-2-ketoglutarate on the accumulation of mRNA regulators of mitochondrial biogenesis and the content of mitochondrial DNA upon suspension of the hindlimbs of rats.