Multiomics Integration Reveals a Metabolic Myopathy in Cardiometabolic HFpEF

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.

Male ZSF1 Obese rats (HFpEF) and Wistar Kyoto (WKY) lean normotensive controls were studied at 26 weeks of age. Gastrocnemius was subjected to bulk RNA-seq, proteomics, metabolomics, and lipidomics analysis. The R package limma 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.

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.

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.