Skeletal muscle enhancer programming of intrinsic cardiorespiratory fitness

Cardiorespiratory fitness (CRF) is a heritable trait associated with improved metabolic health and longevity. Integrating 546 transcriptomic and epigenomic profiles from skeletal muscle of 128 genetically heterogeneous rats selectively bred for high and low running capacity (HCR and LCR), a model that mirrors CRF-associated traits in humans, we identify a distributed enhancer architecture underlying their divergent transcriptomes. Line-divergent alleles were concentrated in distal enhancers: those more active in HCR were enriched for ETS-family transcription factor motifs and positively linked to hundreds of mitochondrial oxidative metabolism and angiogenesis genes, whereas those more active in LCR were enriched for Mef2 motifs and negatively linked to these genes. In 426 genotype, gene expression, and chromatin accessibility profiles from an independent HCRxLCR F2 population (n=147), we validated thousands of these genetic effects. Thus, heritable CRF reflects many enhancers cumulatively tuning energy metabolism and oxygen delivery, providing a molecular basis for variation in CRF.