Recent studies suggest that alterations in skeletal muscle (SM) histology and biochemistry play an important role in determining exercise tolerance in patients with chronic heart failure (CHF). This is highlighted by the finding that exercise training, which represents a consumption (VO2) primarily through adaptations in SM. In this proposal we will examine: 1) possible mechanisms for SM """"""""myopathy"""""""" in CHF, 2) relationship of SM alterations to symptoms and peak V02, 3) role of SM in mediating improvements in peak VO2 and symptoms after exercise training, and 4) the clinical utility of exercise training in varied groups of CHF patients. Studies will examine the relationships between SM enzyme activity, histology, contractile protein expression, and mRNA signalling with peak VO2, SM contractile function, SM metabolism during exercise (via 31P-MRI), and SM oxygenation during exercise (via near infrared-spectrophotometry) in patients with CHF and in normal controls. The following specific hypotheses will be addressed: Hypothesis 1: Alterations in SM metabolism are present during isometric and isotonic exercise in patients with CHF and are related to alterations in SM enzyme activity, histology and contractile protein content. Hypothesis 2: The relationship of SM isometric force to muscle metabolism (measured by 31p-MRI), is altered in CHF. Hypothesis 3: Reduced SM performance in CHF is related to alterations in contractile protein expression and sarcoplasmic reticulum functioning. Hypothesis 4: Alterations in SM protein expression are associated with changes in mRNA expression. Hypothesis 5: Exercise training reverses abnormalities in SM contractility, biochemistry and histology, and improves symptoms and peak VO2 in CHF. Hypothesis 6: In patients with CHF and angina, exercise training coupled with intensive risk factor modifications improves exercise performance and symptoms. Hypothesis 7: Contractile dysfunction in SM is present in patients with CHF and normal LV ejection fractions (diastolic LV dysfunction) and is related to alterations in SM biochemistry and histology.
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