Smyd1 signaling activation improves mitochondrial function and reduces diabetes-associated atrial fibrillation by...

Muscle-specific histone methyltransferase 1 (Smyd1) is required for skeletal and cardiac muscle development, yet its roles and mechanisms in diabetes-associated atrial fibrillation (AF) remain poorly defined. This study aims to elucidate the role of the Smyd1-PGC-1α pathway in the pathogenesis of AF and to investigate the underlying mechanisms. In this study, employing bioinformatic data and in vivo/in vitro experiment, we demonstrated that Smyd1 is significantly down-regulated in the atrium of diabetic mice and in HL-1 cardiomyocytes treated with high-glucose/palmitic acid (HG/PA). This detrimental effect was coincided with diminished PGC-1α transcription and impaired mitochondrial biogenesis, contributing to pathological atrial enlargement, structural and electrical remodeling, fibrosis, lipid droplet accumulation, and increased AF susceptibility. Crucially, Smyd1 overexpression reversed the aforementioned damage. Mechanistically, cardiac-specific overexpression of Smyd1 enhanced mitochondrial biogenesis and respiration by activating PGC-1α transcription and ameliorated HG/PA-induced dysfunction in mitochondrial dynamics and membrane potential. This pathway attenuates high-fat-diet/streptozotocin (HFD/STZ) -induced myocardial injury and reduces susceptibility to diabetes-associated AF. These findings indicate that the Smyd1-PGC-1α axis represents a promising preclinical target that warrants further investigation in human tissues and clinical settings.