Skeletal muscle is a major mass peripheral tissue that accounts for approximately 40% of the total body mass and a major player in energy balance. It accounts for >30% of energy expenditure, is the primary tissue of
insulin stimulated
glucose uptake, disposal, and storage. Furthermore, it influences metabolism via modulation of circulating and stored
lipid (and
cholesterol) flux.
Lipid catabolism supplies up to 70% of the energy requirements for resting muscle. However, initial aerobic exercise utilizes stored muscle
glycogen but as exercise continues,
glucose and stored muscle
triglycerides become important energy substrates. Endurance exercise increasingly depends on
fatty acid oxidation (and lipid mobilization from other tissues). This underscores the importance of
lipid and
glucose utilization as an energy source in muscle. Consequently skeletal muscle has a significant role in
insulin sensitivity, the blood
lipid profile, and
obesity. Moreover, caloric excess,
obesity and physical inactivity lead to skeletal muscle
insulin resistance, a risk factor for the development of type II diabetes. In this context skeletal muscle is an important therapeutic target in the battle against
cardiovascular disease, the worlds most serious public health threat. Major risk factors for cardiovascular disease include
dyslipidemia,
hypertension,
obesity, sedentary lifestyle, and diabetes. These risk factors are directly influenced by diet, metabolism and physical activity. Metabolism is largely regulated by
nuclear hormone receptors which function as
hormone regulated
transcription factors that bind
DNA and mediate the patho-physiological regulation of gene expression. Metabolism and activity, which directly influence
cardiovascular disease risk factors, are primarily driven by skeletal muscle. Recently, many
nuclear receptors expressed in skeletal muscle have been shown to improve
glucose tolerance,
insulin resistance, and
dyslipidemia. Skeletal muscle and
nuclear receptors are rapidly emerging as critical targets in the battle against
cardiovascular disease risk factors. Understanding the function of
nuclear receptors in skeletal muscle has enormous pharmacological utility for the treatment of
cardiovascular disease. This review focuses on the molecular regulation of metabolism by
nuclear receptors in skeletal muscle in the context of
dyslipidemia and
cardiovascular disease.