Hydroxy-methylglutaryl (HMG) CoA reductase inhibitors or statins are the most effective medications for reducing elevated concentrations of low-density lipoprotein cholesterol (LDL-C) and have been documented to reduce cardiac events in both coronary artery disease (CAD) patients and in previously healthy subjects. The Third National Cholesterol Education Program (NCEP III) has presented widely accepted LDL-C treatment goals, but recent clinical trial results and an NCEP Update suggest that these LDL-C treatment goals should be even lower. Consequently, more patients will be treated with higher doses of these medications. Statins have been extremely well tolerated in controlled clinical trails, but are increasingly recognized to produce a skeletal muscle myopathy with symptoms ranging from rhabdomyolysis with renal failure to milder symptoms such as myalgia, cramps and weakness. The reported frequency of such mild symptoms is not clear, and muscle performance has not been examined with these medications. The present study will recruit approximately 440 healthy subjects,3 age 20 to obtain complete study data on 402. Subjects will be randomly assigned to treatment with atorvastatin 80 mg daily or placebo for 6 months of double blind treatment. Handgrip, elbow flexion and knee extension isometric and dynamic strength; knee extension endurance, and maximal aerobic exercise performance with gas analysis will be determined at baseline. Subjects will undergo repeat testing after 6 months of treatment or after meeting the study definition of statin myalgia. Twenty myalgic and 20 asymptomatic subjects will have a quadriceps muscle biopsy performed for histological and ultrastructural muscle morphology (histological and ultrastructural analysis) as well as qRT-PCR, western blotting, and immunohistochemistry to assess candidate genes determined from our prior investigations of statin effects on muscle. Although not included in this application, we will also obtain and store DNA samples for a future comparison of selected genetic polymorphisms (SNPs) between subjects who do or do not develop myopathic symptoms. The results of this study will determine the effect of statins on skeletal muscle strength, endurance, and exercise performance, help determine metabolic pathways involved in statin injury, and may ultimately help develop lipid lowering medications devoid of myopathic effects. [unreadable] [unreadable] [unreadable] [unreadable]