Abstract 512: Cardiac Metabolic Adaptation during Chronic Exercise is Independent of PGC-1 Signaling

Abstract

PGC-1alpha is a transcriptional coactivator that regulates gene expression of mitochondrial proteins and energy metabolic enzymes. In skeletal muscle, PGC-1alpha is induced by endurance training and thought to mediate the energy metabolic adaptation to exercise. We investigated the role of PGC-1alpha signaling in metabolic adaptation of the heart in response to exercise. Male Sprague Dawley rats were trained on treadmills for 10 weeks, resulting in increased left ventricular posterior wall diameter (1.84±0.13 vs. 2.35±0.15 mm, p<0.05), indicating physiological hypertrophy. Gene expression of PGC-1alpha and beta and their transcription factors (NRF1&2, ERRalpha, TFAm) was not different compared to controls. Similarly, expression of OXPHOS genes (Ndufa10, Uqcrc2, COXIV) was unchanged in treadmill-trained hearts. In accordance with gene expression, state 3 respiration of isolated mitochondria was not different from controls, using palmitoyl-carnitine, pyruvate, or glutamate as substrates (natomsO/min/mg protein: Control PC 121±30, Pyr 58±6, Glu 203±42). In contrast, mitochondrial state 3 respiration of the oxidative soleus muscle was tripled with all substrates (natomsO/min/mg protein: PC 150±18 vs. 453±125, Pyr 95±23 vs. 310±37, Glu 115±12 vs. 280±23, p<0.05). Since PGC-1alpha signaling may also regulate substrate oxidation, we investigated oxidation of fatty acids (FAO) and glucose (GO) in the isolated working rat heart using 0.4mM oleate and 5mM glucose. FAO was not different between groups (μmol/min/gdw: 0.99±0.07 vs. 0.92±1.10). While expression of PPARalpha was increased in treadmill trained rats (+49%, p<0.05), FAO genes were not differentially expressed (MCAD, LCAD, CPT1). GO was 40% lower in trained hearts (0.38±0.08 vs. 0.23±0.06 μmol/min/g dry, n.s.) and was accompanied by a trend towards increased PDK4 expression (+90%, p=0.059). The response to insulin was normal. Cardiac power in trained working hearts was also normal. We conclude that PGC-1 signaling may not mediate the cardiac hypertrophic response to exercise. In contrast to skeletal muscle, respiratory capacity is not increased in heart muscle after exercise. The metabolic phenotype of hypertrophied hearts in response to exercise is surprisingly normal.