Decreased sarcomeric mitochondrial creatine kinase 2 impairs skeletal muscle mitochondrial function independently of insulin action in type 2 diabetes

Rizo-Roca, D.; Guimaraes, D. S.; Pendergrast, L. A.; Di Leo, N.; Chibalin, A. V.; Maqdasy, S.; Ryden, M.; Naslund, E.; Ziearth, J. R.; Krook, A.

doi:10.1101/2024.01.11.575194

bioRxiv · 10.1101/2024.01.11.575194

Decreased sarcomeric mitochondrial creatine kinase 2 impairs skeletal muscle mitochondrial function independently of insulin action in type 2 diabetes

Rizo-Roca, D.·Guimaraes, D. S.·Pendergrast, L. A.·Di Leo, N.·Chibalin, A. V.·Maqdasy, S.·Ryden, M.·Naslund, E.·Ziearth, J. R.·Krook, A.

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Abstract

Plasma creatine levels are associated with risk of type 2 diabetes. Since skeletal muscle is the main disposal site of both creatine and glucose, we investigated the role of intramuscular creatine metabolism in the pathophysiology of insulin resistance in type 2 diabetes. We report in men with type 2 diabetes, plasma creatine levels are increased, while intramuscular phosphocreatine content is reduced. These alterations are coupled to reduced expression of sarcomeric mitochondrial creatine kinase 2 (CKMT2). In C2C12 myotubes, Ckmt2 silencing reduced mitochondrial respiration, membrane potential, and glucose oxidation. Electroporation-mediated overexpression of Ckmt2 in skeletal muscle of high-fat diet-fed male mice increased mitochondrial respiration, independent of creatine availability. Thus, beyond the canonical role of CKMT2 on creatine phosphorylation, we reveal a previously underappreciated role of CKMT2 on mitochondrial homeostasis, independent of insulin action. Collectively, our data provides functional evidence into how CKMT2 mediates mitochondrial dysfunction associated with type 2 diabetes.

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Rizo-Roca, D., Guimaraes, D. S., Pendergrast, L. A., Di Leo, N., Chibalin, A. V., Maqdasy, S., Ryden, M., Naslund, E., Ziearth, J. R., Krook, A.. 2024-01-15. Decreased sarcomeric mitochondrial creatine kinase 2 impairs skeletal muscle mitochondrial function independently of insulin action in type 2 diabetes. https://doi.org/10.1101/2024.01.11.575194

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