METTL14-Mediated m6A Methylation Preserves Cardiomyocyte Homeostasis and Attenuates Progeria-Associated Cardiac Remodeling.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder most commonly caused by a de novo synonymous mutation (c.1824C>T) in the LMNA gene. This mutation activates aberrant splicing of prelamin A, leading to the production and accumulation of progerin, which drives accelerated aging, with patients predominantly succumbing to cardiovascular disease. However, while cardiac pathologies are well documented, the cell-autonomous contribution of cardiomyocytes to HGPS-associated cardiac remodeling remains poorly understood. Here, we generated a cardiomyocyte-specific progerin-expressing mouse model (Myh6-Cre; Lmnafl/fl) and found that selective progerin expression in cardiomyocytes was sufficient to recapitulate key cardiac features of HGPS, including myocardial fibrosis, cardiac hypertrophy, and progressive functional decline. Mechanistically, progerin-expressing hearts exhibited a marked reduction in the N6-methyladenosine (m6A) writer components METTL3/14, and knockdown of Mettl3/14 in primary cardiomyocytes decreased the expression of calcium-handling transcript (Casq2), while elevating senescence-related (Cdkn1a and Cdkn2a) and pro-inflammatory transcripts (Ifna and Ifnb). Importantly, cardiomyocyte-targeted restoration of METTL14 partially ameliorated pathological cardiac remodeling and dysfunction in progeroid mice. Together, the data identify METTL14-dependent m6A methylation as a critical regulator of cardiomyocyte integrity during progeria-associated cardiac remodeling. Restoration of cardiac m6A writer activity may represent a potential therapeutic strategy for laminopathy-related cardiovascular aging.