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.

Keywords: PPARδ; heart failure; metabolism; skeletal muscle.

Fig. 1.

Skeletal muscle dysfunction in an animal model with left ventricular dysfunction following myocardial infarction. A: reduced oleic acid oxidation rate in skeletal muscle of animals 8 wk post-myocardial infarction (post-MI). B: decreased ATP content in skeletal muscle tissue in MI mice compared with the sham-operated group. C and D: no differences in succinate dehydrogenase (SDH) or citrate synthase (CS) activity were noted between groups. E: increased TNFα mRNA expression levels in skeletal muscle of MI mice. F and G: muscle fiber cross-sectional area (CSA) analysis. No significant changes in CSA were observed between sham and MI mice. H: decreased running time in the MI group compared with sham-operated mice (*P < 0.05, **P < 0.01, n = 5 per group).

Fig. 2.

In vitro analysis of effects of peroxisome proliferator-activated receptor δ (PPARδ) stimulation. A: reduced fatty acid oxidation rates in response to TNFα stimulation is corrected by PPARδ agonist (GW501516) coincubation but not in response to PPARα agonism (WY14643). B: expression of carnitine palmitoyltransferase-1 (CPT1) decreases under TNFα treatment and increases with coincubation using the PPARδ agonist (C2C12 skeletal muscle myotubes, n = 3 independent experiments per condition. *P < 0.05, **P < 0.01, ***P < 0.001).

Fig. 3.

Effects of PPARδ treatment in an animal model of chronic left ventricular dysfunction following MI. A: increased fatty acid oxidation rate in response to PPARδ stimulation. B: changes in skeletal muscle gene expression with PPARδ stimulation. C: skeletal muscle ATP level changes, P = 0.38. D: no differences in skeletal muscle CSA. E: prolonged running time in animals following MI treated with a PPARδ agonist (*P < 0.05, **P < 0.01; placebo n = 5–9 and GW501516 n = 6 per analysis).