Shared and distinct adaptations to early-life exercise training based on inborn fitness

Authors: SADLER, DANIEL - University Arkansas For Medical Sciences (UAMS); TREAS, LILLIE - Arkansas Children'S Nutrition Research Center (ACNC); ROSS, TAYLOR - Arkansas Children'S Nutrition Research Center (ACNC); SIKES, JAMES - Arkansas Children'S Nutrition Research Center (ACNC); BRITTON, STEVEN - University Of Michigan; KOCH, LAUREN - University Of Toledo; BORSHEIM, ELISABET - University Arkansas For Medical Sciences (UAMS); PORTER, CRAIG - University Arkansas For Medical Sciences (UAMS); BARRE, MARY - Arkansas Children'S Nutrition Research Center (ACNC)

Submitted to: American Journal of Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/24/2025
Publication Date: 6/15/2025
Citation: Sadler, D., Treas, L., Ross, T., Sikes, J., Britton, S., Koch, L., Borsheim, E., Porter, C., Barre, M. 2025. Shared and distinct adaptations to early-life exercise training based on inborn fitness. American Journal of Physiology. https://doi.org/10.1101/2024.12.04.626895.
DOI: https://doi.org/10.1101/2024.12.04.626895

Interpretive Summary: Inherited cardiorespiratory fitness (CRF) influences early life bioenergetics and metabolic health. We tested the hypothesis that early life exercise training would overcome whole-body and tissue metabolic defects imparted by low CRF. At 26 days of age, rat low-capacity runners (LCR, n=20) and high-capacity runners (HCR, n=20) generated by artificial selection were assigned to either sedentary control (CTRL, n=10) or voluntary wheel running (VWR, n=10) for 6 weeks. Our results reveal early life exercise training partially overcomes the metabolic phenotype imparted by low intrinsic CRF, although proteomic adaptations to early exercise training remain influenced by intrinsic CRF.

Technical Abstract: Background: Low cardiorespiratory fitness due to genetics increases the risk for cardiometabolic disease. Endurance exercise training promotes cardiorespiratory fitness and improves cardiometabolic risk factors, but with great heterogeneity. Here, we tested the hypothesis that the metabolic phenotype imparted by low parental (inborn) cardiorespiratory fitness would be overcome by early-life exercise training, and that exercise adaptations would be influenced in part by inborn fitness. Methods: At 26 days of age, male and female rat low-capacity runners (LCR, n=20) and high-capacity runners (HCR, n=20) generated by artificial selection were assigned to either sedentary control (CTRL, n=10) or voluntary wheel running (VWR, n=10) for 6 weeks. Post-intervention, whole-body metabolic phenotyping was performed, and the respiratory function of isolated skeletal muscle and liver mitochondria assayed. Transcriptomics and proteomics were performed on skeletal muscle and liver tissue using RNA-sequencing and mass spectrometry, respectively. Results: Daily VWR volume was 1.8-fold higher in HCR-VWR compared to LCR-VWR. In LCR, VWR reduced adiposity and enhanced glucose tolerance, coincident with elevated total energy expenditure. While intrinsic skeletal muscle mitochondrial respiratory function was unaffected by VWR, estimated skeletal muscle oxidative capacity increased in VWR groups owing to greater mitochondrial content. In the liver, both maximal oxidative capacity and ATP-linked respiration were higher in HCR-VWR than HCR-CTRL. Transcriptomic and proteomic profiling revealed extensive remodeling of skeletal muscle and liver tissue by VWR, elements of which were both shared and distinct based on inborn fitness. Summary: Early-life exercise training partially overcomes the metabolic phenotype imparted by low inborn cardiorespiratory fitness. However, molecular adaptations to VWR are partly influenced by inborn fitness, which may have implications for personalized exercise medicine.