Activation of PPARδ signaling improves skeletal muscle oxidative metabolism and endurance function in an animal model of ischemic left ventricular dysfunction.
Exercise intolerance in heart failure has been linked to impaired skeletal muscle oxidative capacity. Oxidative metabolism and exercise capacity are regulated by PPARδ signaling. We hypothesized that PPARδ stimulation reverts skeletal muscle oxidative dysfunction. Myocardial infarction (MI) was induced in C57BL/6 mice and the development of ventricular dysfunction was monitored over 8 wk. Mice were randomized to the PPARδ agonist GW501516 (5 mg/kg body wt per day for 4 wk) or placebo 8 wk post-MI. Muscle function was assessed through running tests and grip strength measurements. In muscle, we analyzed muscle fiber cross-sectional area and fiber types, metabolic gene expression, fatty acid (FA) oxidation and ATP content. Signaling pathways were studied in C2C12 myotubes. FA oxidation and ATP levels decreased in muscle from MI mice compared with sham- operated mice. GW501516 administration increased oleic acid oxidation levels in skeletal muscle of the treated MI group compared with placebo treatment. This was accompanied by transcriptional changes including increased CPT1 expression. Further, the PPARδ-agonist improved running endurance compared with placebo. Cell culture experiments revealed protective effects of GW501516 against the cytokine-induced decrease of FA oxidation and changes in metabolic gene expression. Skeletal muscle dysfunction in HF is associated with impaired PPARδ signaling and treatment with the PPARδ agonist GW501516 corrects oxidative capacity and FA metabolism and improves exercise capacity in mice with LV dysfunction. Pharmacological activation of PPARδ signaling could be an attractive therapeutic intervention to counteract the progressive skeletal muscle dysfunction in HF.
['Zizola|Cynthia|C|', 'Kennel|Peter J|PJ|', 'Akashi|Hirokazu|H|', 'Ji|Ruiping|R|', 'Castillero|Estibaliz|E|', 'George|Isaac|I|', 'Homma|Shunichi|S|', 'Schulze|P Christian|PC|']
D000255:Adenosine Triphosphate D000818:Animals D002460:Cell Line D004195:Disease Models, Animal D004734:Energy Metabolism D017079:Exercise Tolerance D005227:Fatty Acids D006333:Heart Failure D008810:Mice, Inbred C57BL D053580:Muscle Strength D018482:Muscle, Skeletal D009203:Myocardial Infarction D010084:Oxidation-Reduction D047495:PPAR gamma D010807:Physical Endurance D015398:Signal Transduction D013844:Thiazoles D013997:Time Factors D014158:Transcription, Genetic D018487:Ventricular Dysfunction, Left D016277:Ventricular Function, Left
PPARδ skeletal muscle metabolism heart failure