In both humans and animal models, heart failure is often characterized by skeletal muscle atrophy. This loss of muscle mass can contribute to exercise intolerance and is related to increased morbidity and mortality. The mechanisms underlying skeletal muscle wasting in heart failure, however, are not fully understood. We studied 30 Dahl salt-sensitive rats (10 male, 20 female) fed either a high-salt (HS; 8% NaCl; n=15) or low-salt (LS; 0.6% NaCl; n=15) diet. In this model, HS fed rats develop pressure/volume overload with compensated hypertrophy after 6 wks of diet and progress to heart failure by 8 to 12 wks. LS controls were matched to HS rats for gender and duration of diet. Body mass, food intake, muscle mass and muscle protein and DNA content were measured. In addition, skeletal muscle protein synthesis was assessed by isotope dilution. Muscle tissue was collected from an additional group of 27 rats (HS, n=16; LS; n=11) for RNA analysis. Expression of genes encoding components of the ubiquitin proteasome pathway was assessed by Northern blot and pro- and anti-apoptotic signals by RNase protection assay. Gastrocnemius and plantaris muscles weighed less (16% and 22%, respectively) in HS compared to LS rats (both P<0.01). No differences in soleus or tibialis anterior weights were found. Differences in muscle mass were abolished after data were expressed relative to body size due to the fact that HS rats tended (P=0.094) to weigh less. The lower body mass in HS rats was related to a 16% reduction (P<0.01) in food intake. No differences in protein content, DNA content or the protein-to-DNA ratio were found in gastrocnemius or soleus muscles. Similarly, no differences in muscle protein synthesis were found. The expression of genes for the ubiquitin proteasome pathway did not suggest increased muscle protein breakdown with heart failure. Finally, no differences in the expression of genes for pro- and anti-apoptotic signals or cytokines were observed that might predispose to muscle atrophy. Our results suggest that muscle wasting in heart failure is not associated with alterations in skeletal muscle protein metabolism or the expression of apoptotic genes. Instead, the muscle atrophy observed in this model was related to reduced body weight secondary to decreased food intake. These findings argue against the notion that heart failure is associated with a skeletal muscle myopathy that predisposes to atrophy.