A Model for Crk and CrkL-mediated Downregulation of Circadian Clock Genes for Enhanced Energetic Efficiency and Exercise Tolerance
Location
Philadelphia, PA
Start Date
17-4-2026 1:30 PM
End Date
17-4-2026 2:30 PM
Description
INTRODUCTION: Chicken tumor 10 (CT10) Regulator of Kinase (Crk) and Chicken tumor 10 (CT10) Regulator of Kinase Like (CrkL) are intracellular adaptor proteins that regulate cytoskeletal remodeling, cell adhesion, and signal transduction downstream of receptor tyrosine kinases and integrins. Beyond their established roles in cardiac morphogenesis, evidence suggests that Crk and CrkL may be integrated closely with circadian transcriptional networks and metabolic regulation reflected by an increase in exercise tolerance. Clock genes generally function as 24-hour-regulators of various functions in the body. These genes rhythmically control cardiac signalling, metabolism, electrophysiology, and contractility to optimize efficiency of the cardiomyocytes given the needs of the body correlated with intrinsic sleep/wake cycles. Period circadian clock 2 (PER2) and PER3 are core components of the negative feedback arms of the molecular clock that gate metabolic gene expression, mitochondrial function, substrate utilization, and oxidative capacity in a time-of-day-dependent manner. Likewise, D site albumin promoter binding protein (DBP) is a clock-controlled transcription factor that links circadian oscillations to downstream functions related to lipid metabolism and mitochondrial pathways. Reduction of these functions may attenuate inhibitory feedback within the clock network and enhance metabolic flexibility. Current literature shows that dysregulation of circadian clock genes contributes to cardiac disease. Our lab discovered that Crk and CrkL alters cardiac structure and systemic performance in mice. PER2, PER3, and DPB transcripts are downregulated in hearts of Crk-CrkL-deficient mice while their tolerance to exercise is enhanced. This suggests a disruption of circadian gene expression and its associated metabolic outputs may enhance exercise tolerance by improving the cellular efficiency of metabolism.
OBJECTIVE: Our primary goal is to establish a model of the Crk-CrkL signaling pathway that alters cardiomyocyte circadian gene expression with optimized metabolic performance.
METHODS: Our lab generated mice with epicardial-specific deletion of Crk and CrkL in the epicardium and its derived cells (Crk-CrkL epi+/-). We developed a model to compare exercise tolerance between 3 cohorts of 13-14 week old mice: 1) Crk-CrkL control mice, 2) Crk-CrkL epi+/- mice with strictly controlled circadian cycles, and 3) Crk-CrkL epi +/- mice with dysregulated circadian cycles. All cohorts will exercise on a rodent treadmill with acceleration of speed at 2-minute increments until fatigue is reached. Experiments will be conducted during the dark cycle in mice between 7pm and 1am, which has been established as a time of peak metabolic activity. Total run distance and total run time will be measured as outputs of exercise capacity.
RESULTS: Our gene mapping data reveals associations between Crk-CrkL and circadian clock genes. Our model demonstrates that Crk-CrkL epi+/- mice with the most favorable metabolic gene expression, that has been optimized by a synchronized circadian cycle, will achieve the greatest total treadmill running distance and exercise tolerance among the 3 cohorts.
CONCLUSION: Our bioinformatic analysis of metabolic clock genes shows great promise to link Crk-CrkL expression with modulation of the circadian rhythm. These findings will provide a basis for future investigations into identifying specific pathways of regulation
Embargo Period
5-20-2026
A Model for Crk and CrkL-mediated Downregulation of Circadian Clock Genes for Enhanced Energetic Efficiency and Exercise Tolerance
Philadelphia, PA
INTRODUCTION: Chicken tumor 10 (CT10) Regulator of Kinase (Crk) and Chicken tumor 10 (CT10) Regulator of Kinase Like (CrkL) are intracellular adaptor proteins that regulate cytoskeletal remodeling, cell adhesion, and signal transduction downstream of receptor tyrosine kinases and integrins. Beyond their established roles in cardiac morphogenesis, evidence suggests that Crk and CrkL may be integrated closely with circadian transcriptional networks and metabolic regulation reflected by an increase in exercise tolerance. Clock genes generally function as 24-hour-regulators of various functions in the body. These genes rhythmically control cardiac signalling, metabolism, electrophysiology, and contractility to optimize efficiency of the cardiomyocytes given the needs of the body correlated with intrinsic sleep/wake cycles. Period circadian clock 2 (PER2) and PER3 are core components of the negative feedback arms of the molecular clock that gate metabolic gene expression, mitochondrial function, substrate utilization, and oxidative capacity in a time-of-day-dependent manner. Likewise, D site albumin promoter binding protein (DBP) is a clock-controlled transcription factor that links circadian oscillations to downstream functions related to lipid metabolism and mitochondrial pathways. Reduction of these functions may attenuate inhibitory feedback within the clock network and enhance metabolic flexibility. Current literature shows that dysregulation of circadian clock genes contributes to cardiac disease. Our lab discovered that Crk and CrkL alters cardiac structure and systemic performance in mice. PER2, PER3, and DPB transcripts are downregulated in hearts of Crk-CrkL-deficient mice while their tolerance to exercise is enhanced. This suggests a disruption of circadian gene expression and its associated metabolic outputs may enhance exercise tolerance by improving the cellular efficiency of metabolism.
OBJECTIVE: Our primary goal is to establish a model of the Crk-CrkL signaling pathway that alters cardiomyocyte circadian gene expression with optimized metabolic performance.
METHODS: Our lab generated mice with epicardial-specific deletion of Crk and CrkL in the epicardium and its derived cells (Crk-CrkL epi+/-). We developed a model to compare exercise tolerance between 3 cohorts of 13-14 week old mice: 1) Crk-CrkL control mice, 2) Crk-CrkL epi+/- mice with strictly controlled circadian cycles, and 3) Crk-CrkL epi +/- mice with dysregulated circadian cycles. All cohorts will exercise on a rodent treadmill with acceleration of speed at 2-minute increments until fatigue is reached. Experiments will be conducted during the dark cycle in mice between 7pm and 1am, which has been established as a time of peak metabolic activity. Total run distance and total run time will be measured as outputs of exercise capacity.
RESULTS: Our gene mapping data reveals associations between Crk-CrkL and circadian clock genes. Our model demonstrates that Crk-CrkL epi+/- mice with the most favorable metabolic gene expression, that has been optimized by a synchronized circadian cycle, will achieve the greatest total treadmill running distance and exercise tolerance among the 3 cohorts.
CONCLUSION: Our bioinformatic analysis of metabolic clock genes shows great promise to link Crk-CrkL expression with modulation of the circadian rhythm. These findings will provide a basis for future investigations into identifying specific pathways of regulation
Comments
Presented by Madyson Sobolewski.