Cardiomyocyte BMAL1 deficiency worsens obesity-related cardiomyopathy with heightened PINK1/Parkin-linked mitophagy and mitochondrial dysfunction

Obesity-related cardiomyopathy (OCM) is characterized by pathological cardiac remodeling and progressive functional decline, often accompanied by mitochondrial dysfunction, particularly aberrant mitophagy. The role of the core circadian gene brain and muscle ARNT-like protein 1 (Bmal1) in OCM remains unclear. In this study, we employed a high-fat diet (HFD)-induced OCM mouse model, a cardiomyocyte-specific Bmal1 knockout (Bmal1^CMKO) model, and a palmitic acid (PA)-induced H9c2 cardiomyocyte injury model to investigate the function of Bmal1. In vivo, BMAL1 expression was reduced in hearts of HFD mice; HFD-Bmal1^CMKO mice exhibited exacerbated myocardial hypertrophy, fibrosis, functional impairment, and apoptosis, accompanied by increased expression of the mitophagy-related proteins PINK1, Parkin, and LC3-II. In vitro, PA exposure decreased BMAL1 expression, disrupted mitochondrial membrane potential, increased reactive oxygen species generation, and induced excessive mitophagy; these effects were aggravated by Bmal1 silencing and attenuated by Bmal1 overexpression, which also improved cell viability. Collectively, these findings indicate that Bmal1 plays a protective role in OCM, and its downregulation may be a key contributor to obesity-induced cardiac remodeling and dysfunction. Mechanistically, BMAL1 downregulation was accompanied by activation of the PINK1/Parkin signaling and enhanced mitophagy under lipid stress. By restraining excessive mitophagy and preserving mitochondrial function and metabolic homeostasis, Bmal1 and its associated pathways may represent promising therapeutic targets for OCM.