Low exercise response in hyperglycemic NZO mice is associated with disturbed skeletal muscle BCAA metabolism and upregulation of mitochondrial tRNA synthetases

Research question While regular exercise remains the predominant remedy for the prevention and treatment of type-2 diabetes, not all individuals show considerable improvements in glycemia. We recently showed that in New Zealand Obese (NZO) mice, the response to exercise is dependent on the glycemic state. In contrast to normoglycemic NZO mice (NG), a hyperglycemic subgroup (HG) did not demonstrate improved insulin sensitivity following a chronic training intervention. Here, we investigated the association of plasma amino acid concentrations with skeletal muscle mitochondrial function in the NZO subgroups.

Methods Plasma metabolites of NG and HG NZO mice previously subjected to a high-fat diet and a six-week treadmill training intervention were analyzed using targeted metabolomics. Skeletal muscle mitochondrial function was assessed using transcriptomics and in vitro using Seahorse experiments in C2C12 cells. Significant differences between the groups were determined using two-way ANOVA.

Results Concentrations of the branched-chain amino acids (BCAAs) isoleucine, leucine and valine were markedly elevated in the HG subgroup in response to exercise compared to NG mice. Moreover, gene expression of corresponding mitochondrial tRNA synthetases was upregulated in skeletal muscle of trained HG mice. Knockdown of a selected tRNA synthetase remarkedly improved mitochondrial respiration in C2C12 cells.

Conclusion In conclusion, these results demonstrate that the altered skeletal muscle mitochondrial function in response to exercise and hyperglycemia is accompanied by disturbed BCAA metabolism, contributing to impaired insulin sensitivity. Elevated BCAAs and mitochondrial tRNA synthetases in combination with hyperglycemia may be used as predictive markers for exercise non-response in future precision medicine approaches.

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Publication History

Article published online:
06 May 2021