Autor:innen:
C. Springer (Düsseldorf, DE)
C. Binsch (German Diabetes Center (DDZ), Leibniz Institute for Diabetes Research at Heinrich Heine University Düsseldorf, German Center for Diabetes Research (DZD), DE)
M. Owens (German Diabetes Center (DDZ), Leibniz Institute for Diabetes Research at Heinrich Heine University Düsseldorf, German Center for Diabetes Research (DZD), DE)
D. Herebian (Medical Faculty, University Children's Hospital, Heinrich Heine University Düsseldorf, Düsseldorf, DE)
B. Knebel (German Diabetes Center (DDZ), Leibniz Institute for Diabetes Research at Heinrich Heine University Düsseldorf, German Center for Diabetes Research (DZD), DE)
M. Lienhard (Max Planck Institute for Molecular Genetics (MPIMG), Berlin , DE)
R. Herwig (Max Planck Institute for Molecular Genetics (MPIMG), Berlin , DE)
A. Chadt (German Diabetes Center (DDZ), Leibniz Institute for Diabetes Research at Heinrich Heine University Düsseldorf, German Center for Diabetes Research (DZD), DE)
H. Al-Hasani (German Diabetes Center (DDZ), Leibniz Institute for Diabetes Research at Heinrich Heine University Düsseldorf, German Center for Diabetes Research (DZD), DE)
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.