Chronic heart failure is characterized by changes in skeletal muscle that contribute to exercise intolerance and muscle weakness. The mechanism underlying alterations in the quantity and isoform distribution of key myofibrillar proteins in heart failure, however, has not been identified. To determine if changes in myofibrillar proteins are related to altered gene expression, we measured skeletal muscle myofibrillar mRNA abundance in 9 patients with heart failure (mean ± SE; 63 ± 3 yrs) and 9 controls (70 ± 3 yrs). In addition, we assessed the relationship of circulating levels of anabolic and catabolic hormones, as well as local expression of insulin-like growth factor-I (IGF-I), to myofibrillar mRNA abundance. No differences in muscle mass were found between groups. Heart failure patients were characterized by lower abundance of mRNA encoding the MHC I isoform (-52%; P<0.01); whereas, MHC IIa and MHC IIx mRNA did not differ between groups. Actin mRNA was also lower in heart failure patients compared to controls (-52%; P<0.001). The expression of each MHC isoform transcript correlated with its respective protein product (MHC I: r=0.656, P<0.01; MHC IIa: r=0.489, P<0.05; MHC IIx: r=0.505, P<0.05; n=18 for all). In addition to changes in myofibrillar transcripts, we found a 51% lower (P<0.01) skeletal muscle insulin-like growth factor-1Ea (IGF-1Ea) mRNA content in heart failure patients. Myofibrillar mRNA levels were positively associated with skeletal muscle IGF-1Ea transcript levels (range of r-values: 0.663 to 0.765; P-values: <0.01 to <0.001) and modestly associated with circulating markers of immune activation (range of r-values: -0.487 to -0.555; P-values: <0.05 to <0.03). Our findings suggest that alterations in skeletal muscle MHC content and isoform distribution in heart failure may derive, in part, from changes in MHC gene expression. The relationships of myofibrillar mRNA content to both local and circulating hormones further suggest that alterations in the balance between anabolic and catabolic hormones in heart failure patients may influence skeletal muscle myofibrillar protein phenotype by altering gene expression.