BACKGROUND: Muscle wasting occurs both in chronic heart failure (CHF) and in normal aging and contributes to exercise intolerance and increased morbidity/mortality. However, the molecular mechanisms of muscle atrophy in CHF and their interaction with aging are still largely unknown. We therefore measured the activation of the ubiquitin-proteasome system (UPS) Min muscle biopsies of CHF patients and healthy controls (HC) in two age strata and assessed the age-dependent effects of a 4-week endurance training program on the catabolic-anabolic balance. METHODS AND RESULTS: 60 CHF patients (30 patients <= 55 years, mean age 46 +/- 5 years; 30 patients => 65 years, 72 +/- 5 years) and 60 healthy controls (HC, 30 <= 55 years, 50 +/- 5 years; 30 => 65 years, 72 +/- 4 years) were randomized to 4 weeks of supervised endurance training or to a control group. Before and after the intervention vastus lateralis muscle biopsies were obtained. The expression of cathepsin-L, the muscle-specific E3 ligases MuRF-1 and MAFbx were measured by real-time PCR and confirmed by Western blot. At baseline MuRF-1 expression was significantly higher in CHF patients versus HC (mRNA: 624 +/- 59 versus 401 +/- 25 relative units; p = 0.007). After four weeks of exercise training MuRF-1 mRNA expression was reduced by -32.8% (p = 0.02) in CHF patients <= 55 years and by -37.0% (p < 0.05) in CHF patients => 65 years. CONCLUSIONS: MuRF-1, a component of the ubiquitin-proteasome system involved in muscle proteolysis, is increased in the skeletal muscle of patients with heart failure. Exercise training results in reduced MuRF-1 levels, suggesting that it blocks UPS activation, and does so in both younger and older CHF patients. CLINICAL TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov; identifier NCT00176319.
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