Exercise Training Attenuates MuRF-1 Expression in the Skeletal Muscle of Patients With Chronic Heart Failure Independent of Age The Randomized Leipzig Exercise Intervention in Chronic Heart Failure and Aging Catabolism Study

Background-Muscle wasting occurs in both chronic heart failure (CHF) and 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 and the lysosomal pathway of intracellular proteolysis in muscle biopsies of CHF patients and healthy controls 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-Sixty CHF patients (30 patients aged <= 55 years, mean age 46 +/- 5 years; 30 patients aged >= 65 years, mean age 72 +/- 5 years) and 60 healthy controls (30 subjects aged <= 55 years, mean age 50 +/- 5 years; 30 subjects aged >= 65 years, mean age 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 expressions of cathepsin-L and the muscle-specific E3 ligases MuRF-1 and MAFbx were measured by real-time polymerase chain reaction and confirmed by Western blot. At baseline, MuRF-1 expression was significantly higher in CHF patients versus healthy controls (mRNA: 624 +/- 59 versus 401 +/- 25 relative units; P = 0.007). After 4 weeks of exercise training, MuRF-1 mRNA expression was reduced by -32.8% (P = 0.02) in CHF patients aged <= 55 years and by -37.0% (P < 0.05) in CHF patients aged >= 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 ubiquitin-proteasome system activation and does so in both younger and older CHF patients.