Abstract 2905: Regulation of the Catabolic Ubiquitin-proteasome System in End-stage Chronic Heart Failure: Impact of Physical Exercise Training and Association to Skeletal Muscle Mass
Exercise intolerance is the key symptom in patients (pts) with chronic heart failure (CHF). This is not only the result of central hemodynamic alterations, but also caused by skeletal muscle wasting and atrophy, finally leading to cardiac cachexia. The progressive loss of muscle mass has been partially attributed to an upregulation of the E3 ligases MuRF1 and MAFbx, which activate the muscle ubiquitin-proteasom system and thereby contribute to degradation of muscle proteins. Aim of the present study was to elucidate the effects of regular exercise training on the activation of MuRF1 and MAFbx in the skeletal muscle and their association to skeletal muscle mass in pts with terminal CHF.
Methods: Thirty-seven pts with CHF (NYHA IIIb, LV-EF 24±1 %, peak VO2 15±1 mL/min/kg) due to ischemic (n=20) or dilative cardiomyopathy (n=17) were randomized to 12 weeks (wks) of exercise training (T, n=18) or an inactive control group (C; n=19). At begin (B) and at 12 wks, percutaneous biopsies of the vastus lateralis muscle were obtained, mRNA expression of MuRF1 and MAFbx was quantified by PCR, and protein expression of MuRF1 by Western blot. CT scans from the lower limb were recorded to analyze skeletal muscle cross sectional area (CSA).
Results: Twelve wks of exercise training resulted in a reduction of MAFbx mRNA expression by -29% (from 280±70 to 200±37 rel. units, p<0.05 vs B and C) and of MuRF1 mRNA expression by -39% (from 14.3±2.0 to 8.7±1.4 rel. units, p<0.05 vs B and C), respectively. MuRF1 protein expression decreased by -43% (from 3.5±1.2 to 2.0±0.6 arb. units, p<0.05 vs B and C for change). Exercise training was associated with an increase in muscle CSA by +6% (from 141±5 to 149±5 cm2, p<0.05 vs B and C for change). There was a close, inverse correlation between the reduction of MuRF1 expression and the increase in CSA (r=-0.66, p<0.05). All above mentioned parameters remained unchanged in C.
Conclusion: Physical exercise training in pts with severe CHF reduces the expression of the E3 ligases MuRF1 and MAFbx in the skeletal muscle and hence blunts the activation of the catabolic ubiquitin-proteasom system. This might readjust the balance between peripheral catabolic and anabolic processes in CHF in favour of endogenous muscle regeneration as a result of the training intervention.