Deletion of Sulfonylurea Receptor 2 in the Adult Myocardium Enhances Cardiac Glucose Uptake and Is Cardioprotective

Aubert, Grégory; Barefield, David; Demonbreun, Alexis R.; Ramratnam, Mohun; Fallon, Katherine S.; Warner, James L.; Rossi, Ann E.; Hadhazy, Michele; Makielski, Jonathan C.; McNally, Elizabeth M.

doi:10.1016/j.jacbts.2018.11.012

Cited by 6 publications

(6 citation statements)

References 47 publications

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“…Adult mouse cardiomyocytes were isolated as previously reported [22]. Mice were anesthetized with 5% inhaled isoflurane in 100% oxygen and administered 50 U heparin with an intraperitoneal injection 20 min prior to sacrifice.…”

Section: Cardiomyocyte Isolationmentioning

confidence: 99%

Partial and complete loss of myosin binding protein H-like cause cardiac conduction defects

Barefield

Yamakawa

Tahtah

et al. 2022

Journal of Molecular and Cellular Cardiology

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Section: Cardiomyocyte Isolationmentioning

confidence: 99%

Partial and complete loss of myosin binding protein H-like cause cardiac conduction defects

Barefield

Yamakawa

Tahtah

et al. 2022

Journal of Molecular and Cellular Cardiology

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“…Glucose uptake 2-Deoxyglucose (2-DG) uptake was measured in C2C12 cells using a colorimetric assay kit (ab136955, Abcam) as described previously (87). Briefly, C2C12 cells were plated in a 96-well plate and differentiated for 5 days.…”

Section: Pp2a Immunoprecipitation Phosphatase Assaymentioning

confidence: 99%

Branched-chain ketoacid overload inhibits insulin action in the muscle

Biswas

Dao

Mercer

et al. 2020

Journal of Biological Chemistry

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Branched-chain α-keto acids (BCKAs) are catabolites of branched-chain amino acids (BCAAs). Intracellular BCKAs is cleared by branched-chain ketoacid dehydrogenase (BCKDH), which is sensitive to inhibitory phosphorylation by BCKD kinase (BCKDK). Accumulation of BCKAs is an indicator of defective BCAA catabolism and has been correlated with glucose intolerance and cardiac dysfunction. However, it is unclear whether BCKAs directly alter insulin signaling and function in the skeletal and cardiac muscle cell. Furthermore, the role of excess fatty acids (FA) in perturbing BCAA catabolism and BCKA availability merits investigation. By using immunoblot and UPLC MS/MS to analyze the hearts of fasted mice, we observed decreased BCAA catabolizing enzyme expression and increased circulating BCKAs, but not BCAAs. In mice subjected to diet-induced obesity (DIO), we observed similar increases in circulating BCKAs with concomitant changes in BCAA catabolizing enzyme expression only in the skeletal muscle. Effects of DIO were recapitulated by simulating lipotoxicity in skeletal muscle cells treated with saturated FA, palmitate. Exposure of muscle cells to high concentrations of BCKAs resulted in inhibition of insulin-induced AKT phosphorylation, decreased glucose uptake and mitochondrial oxygen consumption. Altering intracellular clearance of BCKAs by genetic modulation of BCKDK and BCKDHA expression showed similar effects on AKT phosphorylation. BCKAs increased protein translation and mTORC1 activation. Pretreating cells with mTORC1 inhibitor rapamycin restored BCKAs effect on insulin-induced AKT phosphorylation. This study provides evidence for FA mediated regulation of BCAA catabolizing enzymes, BCKA content and highlights the biological role of BCKAs in regulating muscle insulin signaling and function.

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“…During this same period, we observed that the overexpression of a short (55 kDa) splice variant of the sulfonylurea receptor isoform 2A (SUR2A-55) led to cardio-protection and enhanced mitoK ATP activity at rest [11]. In addition, we found that SUR2A-55 associates with glucose handling proteins and may confer cardio-protection via glucose metabolism [14]. However, the complete make up of a SUR2A-55-based mitoK ATP channel is incomplete without a pore forming subunit.…”

Section: Introductionmentioning

confidence: 84%

“…We recently observed that TG SUR2A−55 mice are protected from IR injury [11] and that SUR2A splice variants associate with cardiac glucose transporter proteins and affect glycolysis [14]. Here, we assessed whether the overexpression of SUR2A-55 can lead to increased glucose uptake during myocardial IR injury.…”

Section: Tg Sur2a−55 Mice Have Increased Glucose Uptake During Reperf...mentioning

confidence: 97%

Overexpression of a Short Sulfonylurea Splice Variant Increases Cardiac Glucose Uptake and Uncouples Mitochondria by Regulating ROMK Activity

El-Meanawy

Dooge

Wexler

et al. 2023

Life

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The mitochondrial splice variant of the sulfonylurea receptor (SUR2A-55) is associated with protection from myocardial ischemia-reperfusion (IR) injury, increased mitochondrial ATP sensitive K+ channel activity (mitoKATP) and altered glucose metabolism. While mitoKATP channels composed of CCDC51 and ABCB8 exist, the mitochondrial K+ pore regulated by SUR2A-55 is unknown. We explored whether SUR2A-55 regulates ROMK to form an alternate mitoKATP. We assessed glucose uptake in mice overexpressing SUR2A-55 (TGSUR2A−55) compared with WT mice during IR injury. We then examined the expression level of ROMK and the effect of ROMK modulation on mitochondrial membrane potential (Δψm) in WT and TGSUR2A−55 mice. TGSUR2A−55 had increased glucose uptake compared to WT mice during IR injury. The expression of ROMK was similar in WT compared to TGSUR2A−55 mice. ROMK inhibition hyperpolarized resting cardiomyocyte Δψm from TGSUR2A−55 mice but not from WT mice. In addition, TGSUR2A−55 and ROMK inhibitor treated WT isolated cardiomyocytes had enhanced mitochondrial uncoupling. ROMK inhibition blocked diazoxide induced Δψm depolarization and prevented preservation of Δψm from FCCP perfusion in WT and to a lesser degree TGSUR2A−55 mice. In conclusion, cardio-protection from SUR2A-55 is associated with ROMK regulation, enhanced mitochondrial uncoupling and increased glucose uptake.

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Deletion of Sulfonylurea Receptor 2 in the Adult Myocardium Enhances Cardiac Glucose Uptake and Is Cardioprotective

Abstract: Visual Abstract

Cited by 6 publications

References 47 publications

Partial and complete loss of myosin binding protein H-like cause cardiac conduction defects

Partial and complete loss of myosin binding protein H-like cause cardiac conduction defects

Branched-chain ketoacid overload inhibits insulin action in the muscle

Overexpression of a Short Sulfonylurea Splice Variant Increases Cardiac Glucose Uptake and Uncouples Mitochondria by Regulating ROMK Activity

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