Enhanced skeletal muscle for effective glucose homeostasis

Abstract

As the single largest organ in the body, the skeletal muscle is the major site of insulin-stimulated glucose uptake in the postprandial state. Skeletal muscles provide the physiological foundation for physical activities and fitness. Reduced muscle mass and strength is commonly associated with many chronic diseases, including obesity and insulin resistance. The complications of diabetes on skeletal muscle mass and physiology, resulting from either insulin deprivation or insulin resistance, may not be life-threatening, but accelerate the lost physiological functions of glucose homeostasis. The formation of skeletal muscle commences in the embryonic developmental stages at the time of mesoderm generation, where somites are the developmental milestone in musculoskeletal formation. Dramatic skeletal muscle growth occurs during adolescence as a result of muscle fiber hypertrophy since muscle fiber formation is mostly completed before birth. The rate of growth rapidly decelerates in the late stages of adulthood as adipose tissue gradually accumulates more fat when energy intake exceeds expenditure. Physiologically, the key to effective glucose homeostasis is the hormone insulin and insulin sensitivity of target tissues. Enhanced skeletal muscle, by either intrinsic mechanism or physical activity, offers great advantages and benefits in facilitating glucose regulation. One key protein factor named myostatin is a dominant inhibitor of muscle mass. Depression of myostatin by its propeptide or mutated receptor enhances muscle mass effectively. The muscle tissue utilizes a large portion of metabolic energy for its growth and maintenance. We demonstrated that transgenic overexpression of myostatin propeptide in mice fed with a high-fat diet enhanced muscle mass and circulating adiponectin, while the wild-type mice developed obesity and insulin resistance. Enhanced muscle growth has positive effects on fat metabolism through increasing adiponectin expression and its regulations. Molecular studies of the exercise-induced glucose uptake in skeletal muscle also provide insights on auxiliary substances that mimic the plastic adaptations of muscle to exercise so that the body may amplify the effects of exercise in contending physical activity limitations or inactivity. The recent results from the peroxisome proliferator-activated receptor γ coactivator 1α provide a promising therapeutic approach for future metabolic drug development. In summary, enhanced skeletal muscle and fundamental understanding of the biological process are critical for effective glucose homeostasis in metabolic disorders.

Keywords: Diabetes; Exercise; Glucose homeostasis; Myogenesis; Myostatin; Myostatin propeptide; Skeletal muscle.