title: Activation of PPARδ signaling improves skeletal muscle oxidative metabolism and endurance function in an animal model of ischemic left ventricular dysfunction.
abstract: 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.
authors.affiliation: Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York, New York; and.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Zizola
authors.affiliation: Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York, New York; and.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Kennel
authors.affiliation: Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York, New York; and.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Akashi
authors.affiliation: Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York, New York; and.
authors.forename: Ruiping
authors.initials: R
authors.lastname: Ji
authors.affiliation: Division of Cardiothoracic Surgery, Columbia University Medical Center, New York, New York.
authors.forename: Estibaliz
authors.initials: E
authors.lastname: Castillero
authors.affiliation: Division of Cardiothoracic Surgery, Columbia University Medical Center, New York, New York.
authors.forename: Isaac
authors.initials: I
authors.lastname: George
authors.affiliation: Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York, New York; and.
authors.forename: Shunichi
authors.initials: S
authors.lastname: Homma
authors.affiliation: Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York, New York; and pcs2121@cumc.columbia.edu.
authors.forename: P Christian
authors.initials: PC
authors.lastname: Schulze
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects*; D017079:Exercise Tolerance / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D008810:Mice, Inbred C57BL; D053580:Muscle Strength / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D009203:Myocardial Infarction / Q000150:complications*; D010084:Oxidation-Reduction; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D010807:Physical Endurance / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology*; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D016277:Ventricular Function, Left
chemical_list: D005227:Fatty Acids; C425931:GW 501516; D047495:PPAR gamma; D013844:Thiazoles; D000255:Adenosine Triphosphate
keywords: PPARδ; heart failure; metabolism; skeletal muscle