Differential gene expression in skeletal muscle after induction of heart failure: impact of cytokines on protein phosphatase 2A expression

Different intrinsic alterations of skeletal muscle metabolism and gene expression have been described in chronic heart failure (CHF). As proposed skeletal muscle alterations in CHF may contribute to exercise intolerance and early muscular fatigue. However the exact molecular changes occurring in the skeletal muscle are still unclear. The aim of this study was to characterize the pattern of differential gene expression in an animal model of CHF and to study the regulation of one selected gene. Rats were subjected to LAD ligation or sham operation. mRNA was isolated from musculus quadriceps of both groups and differential gene expression was determined by subtractive hybridization. Quantitative RT-PCR and cell culture experiments were performed to further characterize the changed expression of protein phosphatase 2A (PP2A) in human skeletal muscle biopsies as well as the cytokine dependent regulation of PP2A expression. Out of 800 picked clones differential expression of 24 distinct genes could be identified by sequencing and reverse Northern blotting. PP2A expression demonstrated a significant upregulation in skeletal muscle biopsies from patients with CHF as compared to healthy controls (9.7 +- 1.9 vs. 4.2 +- 0.7 arbitrary units; p<0.05). Incubation of rat skeletal muscle myoblasts with a combination of TNF-(alpha), IL-1(beta), and (gamma)-IFN caused a 3-fold upregulation of PP2A expression vs. untreated cells. These results suggest that CHF is accompanied by changes in expression of genes involved in energy metabolism, contractility, and apoptosis in the skeletal muscle. The upregulation of PP2A, an important regulator in intracellular signaling and apoptosis, may be due to an increase of inflammatory cytokines.