Abstract Estrogen-related receptor gamma (ERRg) is a crucial orphan nuclear receptor that governs cardiac metabolism, mitochondrial function, and contractility. It regulates the expression of genes involved in oxidative phosphorylation, fatty acid b-oxidation and ATP production, providing a sustained energy supply essential for cardiac function. Dysregulation of ERRg has been implicated in pathological cardiac remodelling, including metabolic dysfunctions, hypertrophy and heart failure, highlighting its potential as a therapeutic target for cardiovascular diseases. The purpose of this study is to investigate the regulatory mechanism of ERRg and a membrane protein of gut bacterium Akkermansia muciniphila (Amuc₁100) in cardiac mitochondrial dynamics and energy metabolism. Methods: Two groups of wild-type (WT) and cardiac ERRg-specific knockout (KO) mice underwent a 12-week high-fat diet (HFD) followed by cardiac function assessments using echocardiography and gene expression analysis using q-RT-PCR and immunoblotting analysis. A membrane protein of Akkermansia muciniphila (Amuc₁100) was expressed in human cardiomyocytes (CM) AC16 to determine its interaction with ERRg in cardiac health. Results: Echocardiographic analysis revealed that cardiac-specific depletion of ERRg significantly reduced stroke volume and cardiac output, despite left ventricular (LV) mass remaining unchanged between WT and KO mice. Analysis of key genes involved in mitochondrial energy metabolism revealed that oxidative phosphorylation and fatty acid β-oxidation, including PPARa, CPT1a, ACOX1 and PGC1β, were markedly downregulated in the cardiac tissue of KO mice. Furthermore, regulators of mitochondrial dynamics, such as MFN1 and MFN2 that mediate mitochondrial fusion, were also suppressed in the KO mouse hearts, indicating mitochondrial stress and impaired energy homeostasis. Following a 12-week HFD, both WT and KO mice exhibited a reduction in LV mass, accompanied by a decline in cardiac output. Notably, HFD significantly suppressed the expression of ERRg in the WT mouse hearts and induced the expression of fibrogenic genes, including Stat3, KIF5, BMP4, and TGFβ1/β2, to a more severe extent in KO mice compared to their WT counterparts, suggesting an increased susceptibility of KO mice to cardiac fibrosis. In vitro, expression of Amuc₁100 in human CMs (AC16) upregulated ERRg which was accompanied by increased expression of MFN1, MFN2 and fatty acid b-oxidation genes, indicating the cardioprotective effect of this gut bacterial protein. Conclusion: ERRg interacted with a membrane protein of A. muciniphila to regulate cardiac mitochondrial dynamics and energy metabolism, which provides potential support for a therapeutic strategy targeting cardiovascular disease by manipulating the interaction between host genes i. e. , ERRg and bioactive components of gut bacteria, i. e. , membrane protein of A. muciniphila, Amuc₁100. ERRg and Amuc₁100 in Cardiac Health
Su et al. (Sat,) studied this question.