METTL3 Is Essential for Exercise Benefits in Diabetic Cardiomyopathy.

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Epigenetics

Background:

• Diabetic cardiomyopathy (DiaCM) impairs cardiac function, and while exercise offers benefits, the underlying molecular mechanisms are not fully understood.
• N6-methyladenosine (m6A) RNA modification plays a role in cardiac health and disease, but its specific involvement in DiaCM and exercise response is unclear.

Purpose of the Study:

• To elucidate the role of N6-adenosine-methyltransferase-like 3 (METTL3) and its downstream targets in the cardiac benefits of exercise in diabetic cardiomyopathy (DiaCM).
• To investigate METTL3 and YBX1 as potential therapeutic targets for DiaCM.

Main Methods:

• Investigated METTL3 and m6A levels in human DiaCM patients and induced DiaCM mouse models, assessing exercise effects and METTL3 manipulation (knockout/overexpression).
• Utilized RNA sequencing to identify METTL3 downstream effectors, focusing on YBX1, and examined YBX1's role via overexpression/knockdown in DiaCM cardiomyocytes.
• Assessed the impact of METTL3 activation via small molecules on cardiac function in DiaCM.

Main Results:

• Cardiac METTL3 and m6A levels were reduced in DiaCM patients and mice, but increased with exercise.
• Exercise-induced cardiac benefits in DiaCM were dependent on METTL3; METTL3 overexpression improved cardiac function, while knockout abolished exercise benefits.
• METTL3 enhanced cardiac function by upregulating YBX1 in an m6A-dependent manner, activating Nrf2 and reducing oxidative stress, effects mimicked by YBX1 overexpression and blocked by YBX1 knockdown.

Conclusions:

• METTL3 is essential for the cardioprotective effects of exercise in DiaCM.
• METTL3-mediated upregulation of YBX1 and subsequent Nrf2 activation represent a key mechanism for exercise benefits in DiaCM.
• METTL3 and YBX1 are identified as promising therapeutic targets for treating diabetic cardiomyopathy.