Biochim Biophys Acta. 2015 May;1852(5):873-81.

Sarcoplasmic reticulum Ca2+ ATPase pump is a major regulator of glucose transport in the healthy and diabetic heart.

 

Waller AP1, Kalyanasundaram A2, Hayes S1, Periasamy M3, Lacombe VA4.
  • 1College of Pharmacy, The Ohio State University, USA.
  • 2Department of Physiology and Cell Biology, College of Medicine and Public Health, The Ohio State University, USA.
  • 3Department 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.
  • 4Department of Physiological Sciences, Oklahoma State University, Stillwater, OK, USA. Electronic address: veronique.lacombe@okstate.edu.

 

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.

KEYWORDS: AS160; Biotinylated photolabeled assay; GLUT4; Micropositron emission tomography; SERCA pump

PMID: 25615793

 

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