title: Sarcoplasmic reticulum Ca2+ ATPase pump is a major regulator of glucose transport in the healthy and diabetic heart.
abstract: Despite intensive research, the pathways that mediate calcium (Ca(2+))-stimulated glucose transport in striated muscle remain elusive. Since the sarcoplasmic reticulum calcium ATPase (SERCA) pump tightly regulates cytosolic [Ca(2+)], we investigated whether the SERCA pump is a major regulator of cardiac glucose transport. We used healthy and insulin-deficient diabetic transgenic (TG) mice expressing SERCA1a in the heart. Active cell surface glucose transporter (GLUT)-4 was measured by a biotinylated photolabeled assay in the intact perfused myocardium and isolated myocytes. In healthy TG mice, cardiac-specific SERCA1a expression increased active cell-surface GLUT4 and glucose uptake in the myocardium, as well as whole body glucose tolerance. Diabetes reduced active cell-surface GLUT4 content and glucose uptake in the heart of wild type mice, all of which were preserved in diabetic TG mice. Decreased basal AS160 and increased proportion of calmodulin-bound AS160 paralleled the increase in cell surface GLUT4 content in the heart of TG mice, suggesting that AS160 regulates GLUT trafficking by a Ca(2+)/calmodulin dependent pathway. In addition, cardiac-specific SERCA1a expression partially rescues hyperglycemia during diabetes. Collectively, these data suggested that the SERCA pump is a major regulator of cardiac glucose transport by an AS160 dependent mechanism during healthy and insulin-deficient state. Our data further indicated that cardiac-specific SERCA overexpression rescues diabetes induced-alterations in cardiac glucose transport and improves whole body glucose homeostasis. Therefore, findings from this study provide novel mechanistic insights linking upregulation of the SERCA pump in the heart as a potential therapeutic target to improve glucose metabolism during diabetes.
authors.affiliation: College of Pharmacy, The Ohio State University, USA.
authors.forename: Amanda P
authors.initials: AP
authors.lastname: Waller
authors.affiliation: Department of Physiology and Cell Biology, College of Medicine and Public Health, The Ohio State University, USA.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Kalyanasundaram
authors.affiliation: College of Pharmacy, The Ohio State University, USA.
authors.forename: Summer
authors.initials: S
authors.lastname: Hayes
authors.affiliation: Department of Physiology and Cell Biology, College of Medicine and Public Health, The Ohio State University, USA; Davis Heart and Lung Research Institute, Columbus, OH 43210, USA.
authors.forename: Muthu
authors.initials: M
authors.lastname: Periasamy
authors.affiliation: Department of Physiological Sciences, Oklahoma State University, Stillwater, OK, USA. Electronic address: veronique.lacombe@okstate.edu.
authors.forename: Véronique A
authors.initials: VA
authors.lastname: Lacombe
mesh_terms: D000818:Animals; D001692:Biological Transport; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism*; D004452:Echocardiography; D019788:Fluorodeoxyglucose F18; D020690:GTPase-Activating Proteins / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D006706:Homeostasis; D008822:Mice, Transgenic; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods; D011485:Protein Binding; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism*; D016277:Ventricular Function, Left
chemical_list: C506944:Atp2a1 protein, mouse; D002147:Calmodulin; D020690:GTPase-Activating Proteins; D051275:Glucose Transporter Type 4; C495693:Slc2a4 protein, mouse; C505647:Tbc1d4 protein, mouse; D019788:Fluorodeoxyglucose F18; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D005947:Glucose; D002118:Calcium
keywords: AS160; Biotinylated photolabeled assay; GLUT4; Micropositron emission tomography; SERCA pump