Multiomics Integration Reveals a Skeletal Muscle Metabolic Myopathy in Cardiometabolic HFpEF.
Nov 6, 2026DOI: 10.1161/circheartfailure.125.014126Journal ArticleAHA
Written by: Timothy D AllertonDaniel ArabieKade MaloneAbhishek PanditMahmoud H ElbatreekZhen LiRobert C NolandJake DoironMike KinterBrooke LovelandPravalika JavvadiKirti AgrawalManas R GartiaPraveen Kumar GuttulaTraci T GoodchildSanjiv J ShahSujoy GhoshDavid J Lefer
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: Male ZSF1 Obese rats (HFpEF, n=8) and Wistar Kyoto lean normotensive controls (Control, n=8) were studied at 26 weeks of age. The gastrocnemius was analyzed using bulk RNA sequencing, proteomics, metabolomics, and lipidomics. Differential expression across all omics layers was determined using standard statistical modeling with thresholds of absolute fold‑change >1.5 and FDR <0.05, unless otherwise specified. Additional targeted plasma and skeletal muscle metabolomics and lipidomics were performed in HFpEF and control rats, including analyses of the soleus and the extensor digitorum longus, to validate features associated with predominantly oxidative and glycolytic muscle, respectively.RESULTS: Pathway-level analysis for RNA sequencing and proteomics revealed significant downregulation of oxidative phosphorylation (natural enrichment score (NES), -2.1; P<0.005), electron transport chain (NES, -2.0; P<0.005), and tricarboxylic acid cycle 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 tricarboxylic acid cycle 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-phosphatidylcholine species. Phosphatidylethanolamines species (16:0/16:1-18:0/18:2) were increased.CONCLUSIONS: HFpEF skeletal muscle shows signatures of profound mitochondrial and peroxisomal dysfunction with lipid overload, impaired branched chain amino acid and tryptophan metabolism, and a shift in membrane phospholipid composition, supporting an acquired metabolic myopathy in cardiometabolic HFpEF.
