Loss of RET-ROS at complex I induces diastolic dysfunction in mice that is reversed by aerobic exercise
Ana Vujic1,2, Amy Koo1, Guillaume Bidault3
1Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
Summary
Mitochondrial reactive oxygen species (ROS) generated via reverse electron transport (RET) are crucial for exercise capacity and heart health. Disrupting RET-ROS in mice impaired cardiac function but could be improved with exercise.
Area of Science:
- Cardiovascular Biology
- Mitochondrial Medicine
- Metabolic Physiology
Background:
- Heart failure with preserved ejection fraction (HFpEF) involves redox disruption of metabolic processes.
- The precise mechanisms underlying HFpEF pathogenesis remain incompletely understood.
- Mitochondrial dysfunction is implicated in HFpEF development.
Purpose of the Study:
- To investigate the role of mitochondrial reactive oxygen species (ROS) generated via reverse electron transport (RET) in cardiac metabolism and function.
- To elucidate the mechanisms by which RET-ROS influences exercise capacity and diet-induced metabolic stress.
- To explore therapeutic interventions targeting RET-ROS for improved cardiac health.
Main Methods:
- Utilized a murine model (ND6) with a specific mitochondrial DNA mutation (ND6 G13997A) lacking RET-ROS generation.
- Assessed exercise capacity, response to high-fat/high-sucrose diet, and cardiac function (hypertrophy, diastolic dysfunction).
- Analyzed cardiac metabolite profiles, gene expression, and protein levels of metabolic regulators under basal and dobutamine-induced stress conditions.
- Investigated the effects of forced treadmill running on cardiac metabolism and function in the mutant mice.
Main Results:
- Mice lacking RET-ROS (ND6 mice) exhibited reduced exercise capacity and impaired resilience to dietary stress, despite higher lean body mass.
- ND6 mice developed cardiac hypertrophy with diastolic dysfunction.
- Dobutamine stress revealed elevated succinate and RET-ROS production in wild-type but not ND6 hearts, with altered metabolite profiles in ND6 mice.
- ND6 hearts showed upregulated fatty acid metabolism genes and increased lipid metabolism regulators.
- Exercise training improved metabolic stress and diastolic function in ND6 mice.
Conclusions:
- RET-ROS plays a critical role in regulating exercise capacity and cardiometabolic health.
- Disruption of RET-ROS contributes to cardiac dysfunction and metabolic inflexibility.
- Targeting RET-ROS offers a potential strategy for modulating cardiac metabolism and treating HFpEF.
- Exercise can ameliorate metabolic stress and improve cardiac diastolic function in the context of impaired RET-ROS generation.
