Muscle-specific activation of Ca2+/calmodulin-dependent protein kinase IV increases whole-body insulin action in mice

Abstract

Aims/hypothesis Aerobic exercise increases muscle glucose and improves insulin action through numerous pathways, including activation of Ca2+/calmodulin-dependent protein kinases (CAMKs) and peroxisome proliferator gamma coactivator 1 alpha (PGC-1 alpha). While overexpression of PGC-1 alpha increases muscle mitochondrial content and oxidative type I fibres, it does not improve insulin action. Activation of CAMK4 also increases the content of type I muscle fibres, PGC-1 alpha level and mitochondrial content. However, it remains unknown whether CAMK4 activation improves insulin action on glucose metabolism in vivo. Methods The effects of CAMK4 activation on skeletal muscle insulin action were quantified using transgenic mice with a truncated and constitutively active form of CAMK4 (CAMK4(circle)) in skeletal muscle. Tissue-specific insulin sensitivity was assessed in vivo using a hyperinsulinaemic-euglycaemic clamp and isotopic measurements of glucose metabolism. Results The rate of insulin-stimulated whole-body glucose uptake was increased by similar to 25% in CAMK4(circle) mice. This was largely attributed to an increase of similar to 60% in insulin-stimulated glucose uptake in the quadriceps, the largest hindlimb muscle. These changes were associated with improvements in insulin signalling, as reflected by increased phosphorylation of Akt and its substrates and an increase in the level of GLUT4 protein. In addition, there were extramuscular effects: CAMK4(circle) mice had improved hepatic and adipose insulin action. These pleiotropic effects were associated with increased levels of PGC-1 alpha-related myokines in CAMK4(circle) skeletal muscle. Conclusions/interpretation Activation of CAMK4 enhances mitochondrial biogenesis in skeletal muscle while also coordinating improvements in whole-body insulin-mediated glucose.