Exercise Metabolic Memory Halts Pathological Cardiac Hypertrophy via PDK4

Area of Science:

• Cardiovascular Biology
• Metabolic Regulation
• Epigenetics

Background:

• Pathological cardiac hypertrophy, a precursor to heart failure, is closely linked to impaired glucose metabolism.
• Exercise enhances myocardial glucose utilization, but its long-term effects on metabolic reprogramming and prevention of cardiac hypertrophy are not fully understood.
• This study investigates the sustained metabolic memory induced by exercise-induced hypertrophic preconditioning (EHP) and its cardioprotective mechanisms, focusing on RNA methylation and arachidonic acid metabolism.

Purpose of the Study:

• To elucidate the mechanisms of sustained metabolic memory induced by EHP.
• To understand the role of RNA methylation and arachidonic acid metabolism in EHP-mediated cardioprotection.
• To explore the therapeutic potential of targeting the PDK4-arachidonic acid metabolites axis.

Main Methods:

• Positron emission tomography/computed tomography for cardiac glucose uptake assessment.
• Bulk RNA sequencing for myocardial gene expression profiling.
• Genetic manipulation of Pdk4 (pyruvate dehydrogenase kinase 4) and pressure overload induction via transverse aortic constriction.
• Analysis of RNA methylation, metabolomics, and molecular pathways.

Main Results:

• EHP induced sustained myocardial glucose preference via METTL3-dependent m6A RNA methylation, suppressing Pdk4.
• Pdk4 deletion improved cardiac function and reduced fibrosis under pressure overload, while Pdk4 overexpression abolished EHP's cardioprotection.
• Arachidonic acid metabolites (5-KETE, 12-keto-LTB4, 20-hydroxy-LTB4) were identified as novel inhibitors of hypertrophy and fibrosis by targeting the ERK2/MAPK1 pathway.

Conclusions:

• EHP establishes metabolic memory by suppressing Pdk4 through RNA methylation, altering arachidonic acid metabolism and generating protective lipid mediators.
• Targeting the PDK4-arachidonic acid metabolites axis offers therapeutic potential for mitigating pathological cardiac remodeling and heart failure.