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

May 24, 2026Journal of biomedical research

Lack of BMAL1 in heart muscle cells may worsen obesity-related heart disease by increasing mitochondrial recycling and damage

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Abstract

BMAL1 expression was reduced in hearts of high-fat diet mice, suggesting its potential protective role in obesity-related cardiomyopathy.

High-fat diet-induced obesity led to increased myocardial hypertrophy, fibrosis, functional impairment, and apoptosis in mouse models.
Expression of mitophagy-related proteins PINK1, Parkin, and LC3-II was elevated in the hearts of high-fat diet mice.
Palmitic acid exposure resulted in decreased BMAL1 expression, disrupted mitochondrial function, and increased oxidative stress in cardiomyocytes.
Silencing BMAL1 exacerbated harmful effects on cell viability, while its overexpression improved cell survival under lipid stress.
Downregulation of BMAL1 is associated with the activation of the PINK1/Parkin signaling pathway and excessive mitophagy.

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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 () in OCM remains unclear. In this study, we employed a high-fat diet (HFD)-induced OCM mouse model, a cardiomyocyte-specificknockout () model, and a palmitic acid (PA)-induced H9c2 cardiomyocyte injury model to investigate the function of., BMAL1 expression was reduced in hearts of HFD mice; HFD-mice exhibited exacerbated myocardial hypertrophy, fibrosis, functional impairment, and apoptosis, accompanied by increased expression of the mitophagy-related proteins PINK1, Parkin, and LC3-II., PA exposure decreased BMAL1 expression, disrupted mitochondrial membrane potential, increased reactive oxygen species generation, and induced excessive mitophagy; these effects were aggravated bysilencing and attenuated byoverexpression, which also improved cell viability. Collectively, these findings indicate thatplays 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,and its associated pathways may represent promising therapeutic targets for OCM. Bmal1Bmal1Bmal1Bmal1In vivo Bmal1In vitro Bmal1Bmal1Bmal1Bmal1CMKO CMKO

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

Abstract

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