Metabolic adaptations to acute and chronic exercise

The National Heart, Lung, and Blood Institute (NHLBI) awarded Ursinus College a Project Grant totaling $349,728 under the Cardiovascular Diseases Research program (CFDA 93.837) on September 1, 2025, with completion scheduled for August 31, 2028. This three-year research initiative investigates metabolic adaptations to acute and chronic exercise, with particular focus on understanding how exercise training modulates cardiac metabolism in obese hearts to prevent cardiovascular disease development. The project addresses a critical gap in the literature regarding cardiometabolic responses to exercise, specifically examining sex differences and the mechanisms underlying cardiac lipotoxicity—an imbalance between lipid uptake and oxidation that contributes to cardiomyopathy and heart failure in obese individuals.

The research will be conducted through three specific aims utilizing male and female mouse models: determining the time course of metabolic response to acute exercise, identifying cardiac substrate utilization adaptations from both treadmill and voluntary wheel running protocols, and evaluating exercise training's ability to restore healthy cardiac metabolism in obese hearts. The project generates scientific outputs including novel understanding of sex-specific metabolic responses, characterization of fatty acid and ketone body oxidation pathways in response to exercise intensity, and mechanistic insights into how exercise training may reverse cardiac lipotoxicity. This research supports the NHLBI's mission to advance prevention and treatment of cardiovascular disease through basic science investigation conducted at Ursinus College's facilities in Collegeville, Pennsylvania.

Abstract

Obesity is a major contributor to the development of cardiovascular diseases (CVD), including cardiomyopathy and heart failure. The cardiometabolic profile of the obese heart demonstrates an imbalance between lipid uptake and oxidation, representative of "cardiac lipotoxicity", which is a potential culprit in the development of cardiomyopathy. While exercise training is a recommended non-pharmalogical intervention for primary and secondary prevention of both obesity and CVD, the cardiometabolic adaptations that occur in response to chronic exercise training remain elusive. There are a number of potential concerns that contribute to the inconsistencies in the literature including the time after the last exercise session that metabolism was assessed, the methodologies used to evaluate metabolism, and the exercise training protocols utilized in the studies. Furthermore, studies that specifically explore SEX differences are limited. Therefore, the main objective of this project is to identify and understand the cardiometabolic adaptations in male and female mice in response to acute and chronic exercise. The proposed project will accomplish the objective through three specific aims: 1) to identify the time course of the metabolic response to acute exercise in male and female mice; 2) to identify the adaptations in cardiac substrate utilization and metabolic pathways in response to chronic treadmill running and voluntary wheel running; and 3) to evaluate the ability of exercise training to modulate cardiac metabolism in the obese heart. Within each aim, these three working hypotheses are proposed: 1) the metabolic responses to acute exercise will require greater than 24 hours to return to baseline and will exhibit SEX specific differences; 2) chronic exercise training will enhance fatty acid and ketone body oxidation in an intensity dependent manner; and 3) chronic exercise training will restore the balance of lipid uptake and fatty acid oxidation and improve ketone body oxidation in obese hearts. Overall, the findings from this project have the potential to contribute to the fields of cardiac metabolism and exercise physiology as well as enhance the understanding of the role of exercise training in promoting cardiometabolic health particularly in the setting of obesity and improve the knowledge GAP regarding SEX as a biological variable. Furthermore, the proposed project will provide meaningful experiences in basic research to undergraduate students and allow them to be highly competitive for entry into graduate programs and medical school as well as to pursue careers in biomedical sciences.