Exercise, CaMKII, and type 2 diabetes

Abstract

Individuals who exercise regularly are protected from type 2 diabetes and other metabolic syndromes, in part by enhanced gene transcription and induction of many signaling pathways crucial in correcting impaired metabolic pathways associated with a sedentary lifestyle. Exercise activates Calmodulin-dependent protein kinase (CaMK)II, resulting in increased mitochondrial oxidative capacity and glucose transport. CaMKII regulates many health beneficial cellular functions in individuals who exercise compared with those who do not exercise. The role of exercise in the regulation of carbohydrate, lipid metabolism, and insulin signaling pathways are explained at the onset. Followed by the role of exercise in the regulation of glucose transporter (GLUT)4 expression and mitochondrial biogenesis are explained. Next, the main functions of Calmodulin-dependent protein kinase and the mechanism to activate it are illustrated, finally, an overview of the role of CaMKII in regulating GLUT4 expression, mitochondrial biogenesis, and histone modification are discussed.

Keywords: CaMKII; GLUT4; Type 2 diabetes; exercise; insulin resistance; mitochondrial biogenesis.

Figure 1. Mechanisms of glucose uptake into skeletal muscle: (A) Insulin-activated glucose uptake, (B) Possible mechanisms associated in contraction-stimulated glucose uptake; 1) glucose transportation to the muscle cell, 2) glucose delivery via the membrane, and 3) glucose phosphorylation and then flux through metabolism. CaMK, calmodulin-dependent protein kinase; aPKC, atypical protein kinase C; ROS, reactive oxygen species; AMPK, AMP-activated protein kinase; IRS-1, insulin receptor substrate 1 PI3K, phosphoinositide-3 kinase; G6P, glucose-6-phosphate; NO, nitric oxide and PKB, protein kinase B/Akt

Figure 2. Structure of active CaMKII. Calcium/calmodulin-dependent protein kinase II consists of a catalytic domain, an autoinhibitory domain and an association domain. Binding of calmodulin to CaM binding domain results in a conformational change in CaMKII that exposes the catalytic domain and enables the Thr286 to be phosphorylated.

Figure 3. CaMKII activation by exercise increases GLUT4 expression. Exercise activates the binding of Ca²⁺/calmodulin complex to the CaM binding domain, resulting in the phosphorylation of Thr286 that activates CaMKII. CaMKII activation causes export of HDAC resulting in increased MEF2 gene transcription; and MEF2 together with HAT and other transcriptional factors increase the GLUT4 expression.