Significant evidence suggests that skeletal muscle lipoprotein lipase (LPL) activity is a major determinant of triglyceride and lipoprotein metabolism. It is well documented that exercise training increases skeletal muscle LPL activity, decreases plasma triglycerides, increases HDL-cholesterol, and reduces the incidence of coronary artery disease. The long-term objective of the proposed investigations is to determine, at the level of the LPL gene, the mechanisms(s) by which exercise training increases skeletal muscle LPL mRNA expression.
The first aim of the proposed studies is to systematically establish the time course, exercise duration, and muscles that LPL mRNA is increased in run-trained rats. It is hypothesized that during exercise training, LPL mRNA increases after each exercise session to peak several hours after exercise and then gradually falls to untrained sedentary levels within 24-48 hours of rest. It is also hypothesized that 10 min. of intense running or electrical stimulation of the motor nerve is sufficient to increase skeletal muscle LPL mRNA. These studies will measure the transcription rate of LPL in skeletal muscles of run trained and sedentary control animals. Deletion and mutation experiments on the LPL promoter will determine essential and necessary gene sequences for exercise induced LPL promoter regions. Alternative experiments are planned to test for the involvement of the 3'-untranslated region of LPL in causing the exercise-induced increase in LPL expression. These findings will elucidate the molecular mechanism of increased LPL mRNA levels during exercise training, and thus will be essential for identifying the biochemical signaling pathway(s) involved in exercise increased LPL expression and improved blood lipids.
These specific aims are at the interphase of linking molecular mechanisms regulating LPL expression to the prevention of morbidity and mortality caused by coronary artery disease, the leading cause of death in the United States.
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