Abstract 3795: Readjusting The Catabolic-anabolic Balance In Heart Failure: Beneficial Effects Of Physical Exercise On Protein Catabolism In The Skeletal Muscle
Background: Progressive muscle wasting frequently occurs in the course of chronic heart failure (CHF) and has recently been identified as independent predictor of mortality in clincal studies. However, the molecular mechanisms that mediate muscle catabolism are still largely unknown and no specific pharmacological agents are available to antagonize the loss of muscle mass. We therefore tested the potential of an established anabolic intervention, i.e. exercise training, to prevent cytokine-induced ubiquitin-proteasome-mediated protein degradation in the skeletal muscle of stable patients with advanced CHF.
Methods: 43 CHF-patients and 41 healthy subjects (HS) were prospectively randomized to 4 weeks of supervised bicycle ergometer training at 70% of the heart rate reserve 4 times 20 min/day or to a control group (C). Before and after the intervention a spiroergometry, echocardiography, and skeletal muscle biopsy from the vastus lateralis muscle were performed. Expression of TNF-alpha and the E3 ligase Murf-1, which tags proteins for degradation via the ubiquitin-proteasome system, were quantified by real-time PCR standardized for 18S-rRNA.
In CHF patients (age 60.3 ± 2.9 years, BMI 28.9 ± 1.7, LV-EF 27.4 ± 1.7%): training increased VO2max from 14.9 ± 3.3 to 18.1 ± 4.7 mL/min/kg (p<0.01 vs. C), and LV-EF from 26.8 ± 4.6 to 33.1 ± 5.5% (p=0.001 vs. C). At baseline Murf-1 expression was significantly higher as compared to HS. Training decreased Murf-1 expression from 0.49 ± 0.21 to 0.22 ± 0.07 rel. units (p<0.05) and TNF-alpha expression from 79 ± 7.1 to 44.7 ± 5.9 rel. units (p<0.001).
In HS (age 64.7 ± 2.7 years, BMI 26.2 ± 0.5, LV-EF 63 ± 0.8%) training increased VO2 max from 20.3 ± 2.1 to 27.9.2 ± 1.3 mL/kg min (p=0.01 vs. C). Murf-1 and TNF-alpha expression remained unchanged versus untrained HS.
CHF is associated with local inflammatory and catabolic activation in the skeletal muscle as indicated by higher baseline TNF-alpha and Murf-1 levels.
Training cuts the elevated TNF-alpha and E3-ligase expressions by half within only four weeks of intervention.
These findings emphasize the role of training for the prevention of muscle atrophy and may provide a novel explanation for the prognostic benefits of exercise in CHF.