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

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.