Activation of PPARδ signaling improves skeletal muscle oxidative

245 words) 45 Background Exercise intolerance in heart failure has been linked to impaired 46 skeletal muscle oxidative capacity. Oxidative metabolism and exercise capacity 47 are regulated by PPARδ signaling. We hypothesized that PPARδ stimulation 48 reverts skeletal muscle oxidative dysfunction. 49 Methods Myocardial infarction (MI) was induced in C57BL/6 mice and the 50 development of ventricular dysfunction was monitored over 8 weeks. Mice were 51 randomized to the PPARδ agonist GW501516 (5 mg/kg body weight per day for 52 4 weeks) or placebo 8 weeks post-MI. Muscle function was assessed through 53 running tests and grip strength measurements. In muscle, we analyzed muscle 54 fiber cross-sectional area and fiber types, metabolic gene expression, fatty acid 55 (FA) oxidation and ATP content. Signaling pathways were studied in C2C12 56 myotubes. 57 Results FA oxidation and ATP levels decreased in muscle from MI mice 58 compared to shamoperated mice. GW501516 administration increased oleic 59 acid oxidation levels in skeletal muscle of the treated MI group compared to 60 placebo treatment. This was accompanied by transcriptional changes including 61 increased CPT1 expression. Further, the PPARδ-agonist improved running 62 endurance compared to placebo. Cell culture experiments revealed protective 63 effects of GW501516 against the cytokine-induced decrease of FA oxidation and 64 changes in metabolic gene expression. 65 Conclusion Skeletal muscle dysfunction in HF is associated with impaired 66 PPARδ signaling and treatment with the PPARδ agonist GW501516 corrects 67 oxidative capacity and FA metabolism and improves exercise capacity in mice 68 with LV dysfunction. Pharmacologic activation of PPARδ signaling could be an 69 attractive therapeutic intervention to counteract the progressive skeletal muscle 70 dysfunction in HF. 71