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

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Editor's note
Circadian disruption in heart tissue appears to tip the balance toward excessive mitochondrial recycling in obese hearts, worsening damage rather than preventing it—a mechanistic insight that reframes how we think about metabolic cardiomyopathy. This preliminary mouse study establishes BMAL1 as a brake on pathological mitophagy, an incremental but potentially actionable finding in a crowded field. Cardiologists managing obesity-related heart disease and circadian biologists should take note.

Source: europepmc · Origin: CN · Liu T, Fan X, Zhang N, Wang Y, Qian Z, Hou X, Zhang H, Zou J. · Journal of biomedical research · 2026-05-25

URL: https://pubmed.ncbi.nlm.nih.gov/42178185/

AI rationale (4/5, tier: preliminary): PINK1/Parkin mitophagy mechanism in cardiomyocyte dysfunction directly matches brief INCLUDE criteria; mouse model limits to preliminary tier.

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 ( <i>Bmal1</i>) in OCM remains unclear. In this study, we employed a high-fat diet (HFD)-induced OCM mouse model, a cardiomyocyte-specific <i>Bmal1</i> knockout ( <i>Bmal1</i> <sup>CMKO</sup>) model, and a palmitic acid (PA)-induced H9c2 cardiomyocyte injury model to investigate the function of <i>Bmal1</i>. <i>In vivo</i>, BMAL1 expression was reduced in hearts of HFD mice; HFD- <i>Bmal1</i> <sup>CMKO</sup> mice exhibited exacerbated myocardial hypertrophy, fibrosis, functional impairment, and apoptosis, accompanied by increased expression of the mitophagy-related proteins PINK1, Parkin, and LC3-II. <i>In vitro</i>, PA exposure decreased BMAL1 expression, disrupted mitochondrial membrane potential, increased reactive oxygen species generation, and induced excessive mitophagy; these effects were aggravated by <i>Bmal1</i> silencing and attenuated by <i>Bmal1</i> overexpression, which also improved cell viability. Collectively, these findings indicate that <i>Bmal1</i> 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, <i>Bmal1</i> and its associated pathways may represent promising therapeutic targets for OCM.

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Published 2026-05-28 · Last kit-update 2026-05-28