-Patients with congestive heart failure (CHF) are prone to increased skeletal muscle fatigue. Elevated circulatory concentrations of tumor necrosis factor (TNF)-␣ and monocyte chemoattractant protein-1, which may stimulate matrix metalloproteinase (MMP) activity and, thereby, contribute to skeletal muscle dysfunction, are frequently found in CHF. However, whether skeletal muscle MMP activity is altered in CHF is unknown. Hence, we have used a gelatinase assay to assess the activity of MMP and tissue inhibitors of MMP in single skeletal muscles of rats with CHF 6 wk after induction of myocardial infarction. Sham-operated (Sham) rats were used as controls. We also measured the gene expression and protein contents of MMP-2 and MMP-9 in skeletal muscles of these rats. Plasma MMP activity was nearly seven times higher (P Ͻ 0.05) in CHF than in Sham rats. Concomitantly, the MMP activity within single slow-and fast-twitch skeletal muscles of CHF rats increased two-to fourfold compared with Sham animals, whereas tissue inhibitor of MMP activity did not differ (P Ͼ 0.05). Preformed MMP-2 and MMP-9 were probably activated in CHF, because neither their gene expression nor protein levels were altered (P Ͼ 0.05). Serum concentrations of TNF-␣ and monocyte chemoattractant protein-1 remained unchanged (P Ͼ 0.05) between CHF and Sham rats during the 6-wk observation period. We conclude that development of CHF in rats enhances MMP activity, which in turn may distort the normal contractile function of skeletal muscle, thereby contributing to increased skeletal muscle fatigue. cytokines; fatigue; myocardial infarction PATIENTS WITH CONGESTIVE HEART failure (CHF) experience decreased skeletal muscle fatigue resistance during exercise. To some extent, this can be explained by reduced cardiac output. However, there is no clear relation between exercise intolerance and left ventricular function (8). Fatigue is also more prominent in heart failure patients than in controls when they exercise only a small muscle group, despite the low workload, which requires only a limited cardiac output (34). These findings have prompted investigators to search for abnormalities within the skeletal muscles that could explain their limited exercise capacity. Skeletal muscle alterations, including reduced fatigue resistance, fiber type shift, contractile protein composition, reduced oxidative capacity, and electrolyte handling, have been observed in CHF patients and in animals in experimental models of heart failure, as reviewed by Lunde et al. (16). Then what is causing the skeletal muscle abnormalities observed in CHF?The circulatory levels of TNF-␣ and monocyte chemoattractant protein (MCP)-1 are increased in CHF patients (2, 3). It is possible that increased plasma levels of cytokines can induce acute or chronic changes in skeletal muscle (22). Gielen et al. (7) observed that exercise training reduced the local expression of the proinflammatory cytokines TNF-␣, IL-1, and IL-6 in skeletal muscle of CHF patients. Increased serum levels of inflammato...