Investigating the role of Crk-CrkL genetic deletions on exercise capacity in mice
Location
Philadelphia, PA
Start Date
30-4-2025 1:00 PM
End Date
30-4-2025 4:00 PM
Description
INTRODUCTION: Crk and CrkL genes encode intracellular adaptor proteins that play a role in development of the heart. Investigators have identified their developmental roles in the cardiac neural crest cells for cardiac outflow tract (OTF) septation by regulating apoptosis and smooth muscle differentiation. Mutations and deletions in Crk/CrkL have been linked to several human diseases, including congenital heart diseases that affect the OFT. We identified expression of both proteins in the myocardium, epicardium and epicardial-derived cells (EPDCs) that give rise to the coronary vascular cells and cardiac fibroblasts during embryonic mouse development. Previously, we determined that global deletion of Crk and CrkL in the mouse caused embryonic lethality at mid-gestation due to cardiac structural defects. Using a tissue-specific conditional deletion strategy, we generated mice with epicardial-specific deletions of Crk and CrkL. These Crk/CrkL epi+/- mice survived to adulthood and were subjected to physiological analysis.
OBJECTIVE: Our goal was to investigate the roles of Crk and CrkL in the mammalian heart by examining how they impact cardiovascular function and their potential consequences on systemic performance as demonstrated by exercise endurance.
METHODS: We generated mice with Wilms’ tumor 1-Cre-driven deletion of Crk and CrkL from the epicardium and EPDCs (Crk-CrkL epi+/-). This enabled us to bypass the embryonic lethality caused by global deletion of Crk-CrkL in mice. As a result, we obtained mice with 2-, 3- and 4-allele conditional epicardial deletions of Crk and CrkL. Our lab made physiological comparisons between Crk-CrkL epi+/- mice and Crk-CrkL control mice. Exercise tolerance studies were conducted on 13–14 week old control and Crk-CrkL epi+/- mice by exercising them on a rodent treadmill under fatiguing conditions. We determined their capacity for exercise endurance by measuring the total run distance and total run time of these mice. These values were compared between control and Crk-CrkL epi+/- mice.
RESULTS: Our data indicated that Crk-CrkL epi+/- mice achieved a greater total running distance and a longer period of running time than control mice. Thus, these mice had a higher capacity of exercise endurance than control mice under fatiguing conditions.
CONCLUSION: These results indicate that epicardial-specific deletion of Crk and CrkL enhances exercise endurance in adult mice. We speculate this increase may be related to adaptations of the cardiovascular system to enhance blood flow and delivery to the systemic circulation to support the increased tissue demands at the local level. Future studies will be performed to identify the mechanisms underlying these cardiovascular adaptations.
Embargo Period
5-20-2025
Investigating the role of Crk-CrkL genetic deletions on exercise capacity in mice
Philadelphia, PA
INTRODUCTION: Crk and CrkL genes encode intracellular adaptor proteins that play a role in development of the heart. Investigators have identified their developmental roles in the cardiac neural crest cells for cardiac outflow tract (OTF) septation by regulating apoptosis and smooth muscle differentiation. Mutations and deletions in Crk/CrkL have been linked to several human diseases, including congenital heart diseases that affect the OFT. We identified expression of both proteins in the myocardium, epicardium and epicardial-derived cells (EPDCs) that give rise to the coronary vascular cells and cardiac fibroblasts during embryonic mouse development. Previously, we determined that global deletion of Crk and CrkL in the mouse caused embryonic lethality at mid-gestation due to cardiac structural defects. Using a tissue-specific conditional deletion strategy, we generated mice with epicardial-specific deletions of Crk and CrkL. These Crk/CrkL epi+/- mice survived to adulthood and were subjected to physiological analysis.
OBJECTIVE: Our goal was to investigate the roles of Crk and CrkL in the mammalian heart by examining how they impact cardiovascular function and their potential consequences on systemic performance as demonstrated by exercise endurance.
METHODS: We generated mice with Wilms’ tumor 1-Cre-driven deletion of Crk and CrkL from the epicardium and EPDCs (Crk-CrkL epi+/-). This enabled us to bypass the embryonic lethality caused by global deletion of Crk-CrkL in mice. As a result, we obtained mice with 2-, 3- and 4-allele conditional epicardial deletions of Crk and CrkL. Our lab made physiological comparisons between Crk-CrkL epi+/- mice and Crk-CrkL control mice. Exercise tolerance studies were conducted on 13–14 week old control and Crk-CrkL epi+/- mice by exercising them on a rodent treadmill under fatiguing conditions. We determined their capacity for exercise endurance by measuring the total run distance and total run time of these mice. These values were compared between control and Crk-CrkL epi+/- mice.
RESULTS: Our data indicated that Crk-CrkL epi+/- mice achieved a greater total running distance and a longer period of running time than control mice. Thus, these mice had a higher capacity of exercise endurance than control mice under fatiguing conditions.
CONCLUSION: These results indicate that epicardial-specific deletion of Crk and CrkL enhances exercise endurance in adult mice. We speculate this increase may be related to adaptations of the cardiovascular system to enhance blood flow and delivery to the systemic circulation to support the increased tissue demands at the local level. Future studies will be performed to identify the mechanisms underlying these cardiovascular adaptations.
Comments
Awarded "CCDA Award for Research Excellence" at PCOM Research Day 2025