Abstract Wed085: Voluntary Exercise Training Attenuates Cardiac Hypertrophy Transcriptional Pathways in HFpEF in the Absence of Improvements in Cardiac Metabolism

Background: Exercise (Ex) is a recommended therapy for patients with HFpEF. However, cardiac metabolic adaptations to Ex training are not well understood in HFpEF. Our previous work shows Ex training restores exercise tolerance independent of improvements in cardiovascular function in a “two-hit” HFpEF mouse model. We hypothesized that cardiac metabolic adaptations to Ex training are attenuated in HFpEF mice. Methods: Male C57BL/6N mice (9 weeks of age) were placed on a standard chow diet (Control, n=4/group), a high-fat diet consisting of 60% fat (HFD, n=5/group) or a combination of HFD and 0.5 g/L N(G)-Nitro-L-arginine methyl ester (L-NAME) to induce cardiometabolic HFpEF (n=7/group). At 5 weeks following the various interventions mice were randomized to undergo voluntary wheel running exercise (Ex) or remain in standard cages (Sed) for an additional 5 weeks. Left ventricular (LV) LEAK and OXPHOS capacity respiration rates were determined using high-resolution respirometry (Oroboros) in the presence of 40 µM palmitoylcarnitine and with 1 mM malate, with or without 4 mM ADP. Bulk RNA Seq was performed on cardiac muscle to determine the transcriptional response to Ex training. Bioinformatic analysis was conducted using Ingenuity Pathway Analysis (IPA, Qiagen). Results: Ex training increased (p=0.02) the respiratory control ratio (RCR, OXPHOS/LEAK) in HFD Ex (1.9 ± 0.5) vs HFD Sed mice (3.2 ± 1.4). LV OXPHOS and pyruvate supported respiration were higher (41&83%), but not statistically significant (p=0.10&p=0.06) in HFD Ex mice. Whereas the HFpEF Ex mice did not show an increase in LV FAO in any respiratory state or RCR. RNA seq revealed that Ex training resulted in a significant downregulation (p<0.001, z-score=-2.4) of genes associated with oxidative phosphorylation in HFpEF Ex vs HFpEF Sed mice. Cardiac hypertrophic pathway signaling was significantly activated in HFpEF Sed mice (p=0.009, z-score =0.4) which was reversed in HFpEF Ex mice (p=0.001, z-score = -2.0). Conclusion: The Ex-training adaptation to increase LV RCR and OXPHOS for fatty acids were present in obese (HFD) mice but suppressed in HFpEF mice. The downregulation of OXPHOS gene expression pathways may potentially explain the blunted adaptive response to Ex training in HFpEF mice. Notably, cardiac hypertrophic signaling was reversed in HFpEF mice following voluntary exercise training.