Key result
Cardiometabolic HFpEF is linked to severe skeletal muscle mitochondrial dysfunction and impaired oxidative phosphorylation.
Why the study?
Comprehensive profiling of metabolic pathways underlying skeletal muscle dysfunction in HFpEF had not been conducted to identify viable targets for treating exercise intolerance.
Effect estimate: NES -2.1
p-value: p=<0.005
Metabolic profiling may identify targets for exercise intolerance in HFpEF; leaves open whether pathway modulation improves outcomes.
Background: Skeletal muscle dysfunction is a major peripheral determinant of exercise intolerance and physical disability in heart failure with preserved ejection fraction (HFpEF). Metabolic and mitochondrial dysfunction are considered to be key components of skeletal muscle dysfunction, but comprehensive profiling of metabolic pathways has not been conducted. Elucidation of dysregulated metabolic pathways is essential to determine viable targets for the treatment of exercise intolerance in HFpEF. Methods: was used to determine differential expression in all omics layers (absolute fold-change>1.5, FDR0.05, unless otherwise indicated). Additional targeted plasma and skeletal muscle (soleus and EDL) metabolomics and lipidomics were performed on HFpEF and control rats. Results: Pathway level analysis for RNA seq and proteomics revealed significant downregulation of oxidative phosphorylation (NES -2.1, p<0.005), electron transport chain (NES -2.0, p<0.005), and TCA cycle (-1.8, p<0.05). The most upregulated pathways were PPAR signaling (NES 2.2, p<0.0001), tryptophan metabolism (NES 1.8, P<0.005), and amino acid oxidation (NES 1.8, p<0.005) pathways. Metabolomics revealed an accumulation of TCA cycle intermediate, isocitrate, and phosphate reduction. Branched-chain amino acids were significantly increased, whereas amino acids related to tryptophan metabolism were reduced and shifted towards increased serotonin accumulation. Phospholipid species were differentially regulated with increased palmitoylated phosphatidylcholines but reduced arachidonoyl-PC species. Phosphatidylethanolamines (PE) species (16:0/16:1-18:0/18:2) were increased. Conclusion: Our multiomics analysis of skeletal muscle in HFpEF revealed severe mitochondrial dysfunction that was characterized by reduced complex I and II activity. Mitochondrial and peroxisomal lipid overload results in a shift in membrane phospholipid accumulation and composition. Reduced BCAA oxidation and dysregulation of tryptophan metabolism are key features of amino acid metabolism that reduce anaplerosis and promote the accumulation of toxic metabolites. Comparative analysis of other skeletal muscle disorders suggests that an acquired metabolic myopathy exists in cardiometabolic HFpEF.
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A 2025 study studied Heart failure with preserved ejection fraction (HFpEF) (n=21). Cardiometabolic HFpEF (ZSF1 Obese phenotype) vs. Wistar Kyoto (WKY) lean normotensive controls was evaluated on Downregulation of oxidative phosphorylation pathway (RNA-seq and proteomics) (NES -2.1, p=<0.005). Cardiometabolic HFpEF in ZSF1 obese rats was associated with severe skeletal muscle mitochondrial dysfunction, including significant downregulation of oxidative phosphorylation (NES -2.1, p<0.005).
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