FTO-Eci1 Axis Mediates Exercise-Induced Cardioprotection in Pressure Overload Mice.

Area of Science:

• Cardiovascular Physiology
• Molecular Biology
• Epigenetics

Background:

• Regular exercise improves cardiac function and metabolism.
• N6-methyladenosine (m⁶A) RNA modification is vital for myocardial homeostasis.
• Fat mass and obesity-associated protein (FTO) is a key demethylase in myocardial remodeling, but its role in exercise-induced cardiac protection is unknown.

Purpose of the Study:

• To investigate the role of FTO in exercise-induced heart protection.
• To identify FTO's molecular targets and mechanisms in the context of cardiac pressure overload and exercise.

Main Methods:

• Transverse aortic constriction (TAC) mouse model with six weeks of treadmill exercise.
• Analysis of m⁶A levels and methylation enzymes, including FTO.
• High-throughput sequencing to identify FTO target genes, with subsequent in vivo validation using cardiac-specific Eci1 knockout mice.

Main Results:

• Exercise increased FTO expression in TAC mouse hearts, and reducing FTO diminished exercise benefits.
• Differential m⁶A-modified genes were enriched in fatty acid metabolism pathways; exercise reversed abnormal lipid accumulation.
• FTO regulates enoyl-CoA delta isomerase 1 (Eci1) expression via m⁶A modification, impacting cardiac function and lipid metabolism.

Conclusions:

• FTO plays a crucial role in mediating exercise-induced cardioprotection.
• FTO modulates Eci1 expression through m⁶A-dependent mechanisms, enhancing fatty acid metabolism.
• FTO's action mitigates pressure overload-induced heart failure during exercise.