The pathobiochemical role of the dystrophin-dystroglycan complex and the Ca2+-handling apparatus in diabetes-related muscle weakness (Review)

Serious diabetic complications affect millions of patients worldwide. Skeletal muscle represents the largest insulin-regulated glucose sink in the body, making insulin resistance and abnormal glucose disposal in muscle fibres a critical aspect of diabetes mellitus. Advances in the biomedical analysis of the molecular mechanisms underlying diabetic complications rely heavily on the study of suitable disease models. The Goto-Kakizaki (GK) rat is an established animal model of non-obese type 2 diabetes. This review discusses the recent finding that expression of the dystrophin-dystroglycan complex is drastically altered in diabetic GK skeletal muscle fibres. In normal muscle, the dystrophin-glycoprotein complex provides a stabilizing connection between the actin membrane cytoskeleton and the extracellular matrix component laminin. A reduction in dystrophin-associated proteins may be associated with a weakening of the fibre periphery, abnormal sarcolemmal signaling and/or a decreased cytoprotective mechanism in diabetic skeletal muscle. Stimulation by insulin might be altered due to impaired linkage between the dystrophin-anchored actin cytoskeleton and the intracellular pool of essential glucose transporters. The diminished recruitment of GLUT4 transporter molecules to the sarcolemma may be a key step in the development of insulin resistance in diabetic skeletal muscles. Thus, analogous to certain forms of muscular dystrophy, altered dystrophin levels may have pathological effects in type 2 diabetes. In contrast, the dystrophin-glycoprotein complex does not appear to be altered in diabetic cardiac muscle. However, reduced expression of the sarcoplasmic reticulum Ca2+-ATPase isoform SERCA2 is characteristic of cardiac abnormalities in type 2 diabetes. Reduced Ca2+ removal from the sarcoplasm may be associated with impaired relaxation kinetics, and could therefore play a pathophysiological role in diabetic cardiomyopathy. Here, the potential impact of these molecular alterations in diabetic muscle tissues is discussed and critically examined with respect to the future design of alternative treatment strategies to counteract diabetes-associated muscle weakness.