The Exocyst Complex Coordinates GLUT4 and CD36 Trafficking and Fuel Uptake in Cardiomyocytes
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2024
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Increasing the rate of glucose metabolism in the heart muscle protects against cardiomyocyte injury triggered by low oxygen levels, such as during myocardial ischemia. Molecules that promote a shift toward glucose uptake and glycolytic metabolism in heart muscle, thus improving metabolic function and decreasing ischemic injury, represent attractive therapeutic targets.Substrate uptake via glucose transporters and fatty acid translocase on the cell membrane is the first key governing step of substrate metabolism in heart muscle. Levels of the predominant glucose transporter GLUT4 and the fatty acid translocase CD36 on the cardiomyocyte surface increase in response to elevated insulin levels following a meal or via the activation of AMP-activated protein kinase (AMPK) during exercise or energy requirement. It has been established that in adipocytes, the highly conserved, eight-protein exocyst trafficking complex is required for insulin-induced GLUT4 membrane delivery and glucose uptake, and our recent work showed that the exocyst is necessary for insulin- and AMPK-induced GLUT4 and CD36 trafficking in skeletal muscle cells as well. The exocyst is responsible for the targeted delivery of membrane-bound vesicles by docking them to the intracellular surface of the cell membrane prior to their fusion. However, despite the high expression of exocyst subunits in cardiac muscle, the mechanisms by which the exocyst trafficking complex directs glucose transporter delivery to the cardiomyocyte cell surface presented a gap in our knowledge.
The overall goal of this study set out to determine how the exocyst regulates GLUT4 and CD36 membrane trafficking in heart muscle cells in response to insulin and AMPK induction and, additionally, how exocyst-mediated trafficking of these transporters contributes to the shift towards glucose utilization during ischemia.
Our work has demonstrated that the exocyst is a key component in insulin- and contraction-stimulated glucose and long chain fatty acid (LCFA) uptake in cardiac muscle cells. The exocyst inhibitor endosidin-2 (ES2) impaired induced exocyst assembly and recruitment to GLUT4 and CD36, trafficking of CD36 to the cell surface, and glucose and LCFA uptake in H9c2 cardiomyoblasts.
Moreover, in response to both hypoxia and stimulated ischemia, we observed a demand for the exocyst at the mRNA and protein level in these cardiac myoblasts. ES2 inhibition in H9c2 cells hindered hypoxia-induced exocyst assembly and recruitment to GLUT4 as well glucose uptake.
From our results we conclude that the exocyst complex has a critical role in stimulated glucose and fatty acid uptake in cardiac myocytes. We conclude that our research on the exocyst complex presents new insights into potential therapeutics for cardiac ischemic injury.
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Cellular biology, Molecular biology, Biology, cardiomyocytes, CD36, exocyst, GLUT4, hypoxia, ischemia
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142 pages
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