Skeletal muscle enhancer programming of cardiorespiratory fitness

Abstract

Cardiorespiratory fitness (CRF) is a heritable trait associated with improved metabolic health and longevity. To identify regulatory mechanisms underlying CRF, we integrated 546 transcriptomic and epigenomic profiles from skeletal muscle of 128 genetically heterogeneous rats selectively bred for high and low running capacity, a model that mirrors CRF-associated traits in humans. Selection drove genetic convergence in coordinated skeletal muscle enhancer networks linked to lipid metabolism and angiogenesis genes. We validated thousands of these genetic effects through integration of 426 genotype, gene expression, and chromatin accessibility profiles in an independent HCRxLCR F2 population (n=147). These 972 multi-omics profiles show that CRF-associated genetic variation reshapes the chromatin landscape to support energy metabolism and oxygen delivery, offering a molecular framework for identifying targets to reduce cardiometabolic disease risk.