Abstract 18701: Activation of PPAR Delta Signaling Corrects Impaired Skeletal Muscle Oxidative Metabolism in Heart Failure

Abstract

Background Exercise intolerance in heart failure (HF) has been linked to impaired skeletal muscle oxidative capacity. PPARδ signaling regulates oxidative metabolism and exercise capacity. We hypothesized that decreased skeletal muscle oxidative capacity in HF can be reverted by PPARδ agonists. Methods Left ventricular (LV) dysfunction was induced in C57BL/6 mice by left coronary artery ligature and confirmed by echocardiography. At 11 weeks post-MI, mice received the PPARδ agonist GW501516 (5 mg/kg body weight per day for 14 days, n=6) or vehicle (con, n=6). Exercise function was tested by swimming tests. Following sacrifice, skeletal muscle was harvested for RT-PCR, fatty acid (FA) and glucose oxidation assays, and ATP tissue content analysis. Cell culture analysis of signaling pathways was performed in C2C12 myotubes. Results Cardiac function decreased following MI (fractional shortening: 15.9±6.% vs 29.9±6.6% in sham; p<0.001). FA oxidation was reduced in quadriceps muscle in MI mice (2.5±1.0 vs 4.0±0.8 pmol/mg tissue in sham; p=0.04) with a trend in glucose oxidation (-27%; p=0.07). Muscle ATP content decreased following MI (3.3±1.7 vs 6.1±1.1 uM ATP/ug protein in sham; p<0.01). Expression of metabolic marker genes CPT1 (-86%), PDK4 (72%) and PGC1a (-94%) decreased in muscle post-MI (all p<0.05). 2 weeks GW501516 administration increased muscle FA oxidation in animals with LV dysfunction (3.9±1.6 vs 1.8±0.4 pmol oleic acid/mg tissue in con; p=0.04) and also increased CPT1 expression by 309±175% (p<0.001). There was a non-significant increase (+11%) in swimming duration in the GW501516 group. Treatment of C2C12 myotubes with 5 µM GW501516 protected from TNFα (25 ng/ml)-dependent decrease in FA oxidation (129.2±2.5 vs 237.8±6.8 pmol oleic acid/mg protein in TNFα+ GW501516 ; p<0.001) Further, GW501516 prevented TNFα -dependent decrease in CPT1 expression (255±39 vs 58±5 % in TNFα alone, p<0.01). Conclusion Treatment with the PPARδ agonist GW501516 corrects the impaired skeletal muscle oxidative capacity and metabolism in mice with ischemic LV dysfunction. Pharmacologic activation of PPARδ signaling could be an attractive intervention to counteract the progressive skeletal muscle dysfunction in HF.