Activation of PPARδ signaling improves skeletal muscle oxidative metabolism and endurance function in an animal model of ischemic left ventricular dysfunction
Open Access
- 1 May 2015
- journal article
- Published by American Physiological Society in American Journal of Physiology-Heart and Circulatory Physiology
- Vol. 308 (9), H1078-H1085
- https://doi.org/10.1152/ajpheart.00679.2014
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.This publication has 39 references indexed in Scilit:
- Angiopoietin-Like 4 Mediates PPAR Delta Effect on Lipoprotein Lipase-Dependent Fatty Acid Uptake but Not on Beta-Oxidation in MyotubesPLOS ONE, 2012
- DGAT1 deficiency decreases PPAR expression and does not lead to lipotoxicity in cardiac and skeletal muscleJournal of Lipid Research, 2011
- Repeated transient mRNA bursts precede increases in transcriptional and mitochondrial proteins during training in human skeletal muscleJournal Of Physiology-London, 2010
- Alterations in peroxisome proliferator-activated receptor mRNA expression in skeletal muscle after acute and repeated bouts of exerciseMolecular and Cellular Biochemistry, 2009
- PPARδ Agonism Activates Fatty Acid Oxidation via PGC-1α but Does Not Increase Mitochondrial Gene Expression and FunctionJournal of Biological Chemistry, 2009
- Muscle-Derived Angiopoietin-Like Protein 4 Is Induced by Fatty Acids via Peroxisome Proliferator–Activated Receptor (PPAR)-δ and Is of Metabolic Relevance in HumansDiabetes, 2009
- AMPK and PPARδ Agonists Are Exercise MimeticsCell, 2008
- Analysis of global mRNA expression in human skeletal muscle during recovery from endurance exerciseThe FASEB Journal, 2005
- Muscle fiber type I influences lipid oxidation during low‐intensity exercise in moderately active middle‐aged menScandinavian Journal of Medicine & Science in Sports, 2004
- Regulation of Muscle Fiber Type and Running Endurance by PPARδPLoS Biology, 2004