Key result
Myocardial GRK2 upregulation causes ~2-fold higher palmitate-induced cardiomyocyte death and impairs mitochondrial respiration.
Why the study?
GRK2 is localized to mitochondria, but its role in mitochondrial function and metabolism remains not clearly defined.
Does myocardial GRK2 upregulation impair fatty acid metabolism, cell survival, and β-adrenergic receptor-mediated mitochondrial respiratory responses in adult cardiomyocytes?
Does myocardial GRK2 upregulation impair fatty acid metabolism, cell survival, and β-adrenergic receptor-mediated mitochondrial respiratory responses in adult cardiomyocytes?
Answers are grounded in this paper and cite their sources.
Demonstrates that myocardial GRK2 upregulation directly impairs cardiomyocyte fatty acid catabolism and blunts β-adrenergic-stimulated mitochondrial respiratory adaptation even in the absence of prior cardiac injury, highlighting mitochondrial GRK2 as a potential metabolic target in heart failure.
G-protein coupled receptor (GPCR) kinase 2 (GRK2) is upregulated in heart failure (HF) patients and mouse models of cardiac disease. GRK2 is a regulator of β-adrenergic receptors (βARs), a GPCR involved in ionotropic and chronotropic responses. We and others have recently reported GRK2 to be localized in the mitochondria, although its function in the mitochondria and/or metabolism remain not clearly defined. We hypothesized that upregulation of GRK2 reduced mitochondrial respiratory function and responses to βAR activation. Utilizing isolated mouse primary adult cardiomyocytes (ACMs), we investigated the role of glucose, palmitate, ketone bodies, and BCAAs in mediating cell survival. Our results showed that myocyte upregulation of GRK2 promotes palmitate-induced cell death. Isotopologue labeling and mass spectrometry showed that the upregulation of GRK2 reduces β-hydroxybutyryl CoA generation. Next, using isoproterenol (ISO), a non-selective βAR-agonist, we determined mitochondrial function in mouse and human primary ACMs. Upregulation of GRK2 impaired ISO-mediated mitochondrial functional responses, which we propose is important for metabolic adaptations in pathological conditions. Increased cardiac levels of GRK2 reduced fatty acid-specific catabolic pathways and impaired ISO-stimulated mitochondrial function. Our data support the notion that GRK2 participates in bioenergetic remodeling and may be an important avenue for the development of novel pharmacological strategies in HF.
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Zhai et al. (2022) studied Heart failure and myocardial metabolic remodeling. Cardiac-specific GRK2 overexpression and isoproterenol stimulation vs. Non-littermate control (NLC) mice and saline/vehicle control was evaluated on Palmitate-induced adult cardiomyocyte cell death, fatty acid metabolic flux (3-hydroxybutyryl-CoA generation), and mitochondrial oxygen consumption rates (OCR). Myocardial GRK2 upregulation increased palmitate-induced cardiomyocyte death by ~2-fold, reduced 3-hydroxybutyryl-CoA generation, and depressed isoproterenol-stimulated mitochondrial respiration.
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