Abstract Body: Background: Skeletal muscle (Skm) metabolic dysfunction is a major driver of exercise intolerance and reduced functional capacity in heart failure with preserved ejection fraction (HFpEF). While the cardiac features of HFpEF are well-documented, the metabolic mechanisms driving Skm dysfunction have not been elucidated. Additionally, the effects of standard-of-care clinical therapy, such as sodium-glucose cotransporter 2 inhibitors (SGLT2i), on Skm metabolism have yet not been investigated in HFpEF.

Methods: We performed global metabolomic analysis on skeletal muscle (gastrocnemius) of ZSF1 Obese (Ob, HFpEF, n=7) rats treated with Empagliflozin (EMPA, 10 mg/kg/day) for 8 weeks starting at 10 weeks of age. EMPA-treated rats were compared to age-matched ZSF1 Ob (n=8) and Wistar Kyoto (WKY, n=5) control rats (i.e., lean normotensive).

Results: Skm of ZSF1 Ob rats demonstrated increased (p<0.05) accumulation (3.7 ± 1.7 fold change (FC)) of medium and long-chain fatty acylcarnitine species. Increased palmitoylated phospholipids such as phosphatidylcholine (PC, 1.5 ± 0.6 FC) and phosphatidylethanolamine (PE, 2.1 ± 0.9 FC) were also detected in ZSF1 Ob compared to WKY control rats. EMPA treatment reversed the accumulation of fatty acid species (0.6 ± 0.3 FC), palmitoylated PC (0.7 ± 0.3 FC), and PE (0.7 ± 0.1 FC). Skeletal muscle levels of the branched-chain amino acids (BCAA, leucine, isoleucine, and valine) were significantly increased in ZSF1 Ob vs. WKY rat SKM (average of all BCAAs, 1.6 ± 0.4 FC, p<0.05). EMPA treatment did not significantly reduce skeletal muscle BCAA levels but increased the BCAA catabolites isovalerylcarnitine (3.1 FC, p<0.005) and beta-hydroxyisovaleroylcarnitine (1.5 FC, p<0.001).

Conclusion: The accumulation of fatty acids (acylcarnitines and phospholipids) and BCAAs is a metabolic signature of Skm dysfunction in a well-characterized rodent model of severe cardiometabolic HFpEF. We demonstrate that SGLT2i therapy with Empagliflozin reverses the accumulation of fatty acids and increases the catabolism of BCCA in the Skm. These results suggest a potential mechanism related to the clinical efficacy of SGLT2i treatment to improve physical function and exercise capacity in HFpEF patients.