Home » Key Drug Discovery Articles » Sarcoplasmic reticulum Ca(2+) ATPase pump is a major regulator of glucose transport in the healthy and diabetic heart

Sarcoplasmic reticulum Ca(2+) ATPase pump is a major regulator of glucose transport in the healthy and diabetic heart

Significance Statement

 

Diabetes mellitus is a significant health problem affecting both humans and animals. In humans, the incidence of both diabetes and cardiovascular diseases is anticipated to increase to epidemic levels in both the industrial and developing worlds over the next 2 decades. The landmark of diabetes is sustained hyperglycemia resulting from dysfunctional glucose uptake into insulin-sensitive tissues (i.e., cardiac and skeletal muscles, and adipose tissues), which causes multi-organ dysfunction. Importantly, diabetes is a major cause of heart disease, and heart failure is the cause of death in ~ 65% of Type 1 diabetic patients. Yet despite this high prevalence, the mechanisms that result in cardiac dysfunction are poorly understood.

The translocation of glucose transporter (GLUT)-4 protein (main isoform) from an intracellular (non active) pool to the cell surface (active site) increases glucose transport, and is largely regulated by insulin- and Ca2+/contraction- dependent processes. The mechanisms by which Ca2+ regulates GLUT4 trafficking in the heart is poorly understood however, and the mechanisms by which glucose transport is down-regulated in the diabetic myocardium are not well known.  One of the main reasons for this is the technical challenges associated with the study of glucose transport in the heart, therefore in the present study we utilized an innovative photolabeling technique, which provides a direct and easily quantifiable measure of active cell surface GLUTs in intact perfused mouse heart, thus eliminating a critical barrier to progress in the field of cardiac metabolism.

Overall the present study provides novel evidence demonstrating that sarcoplasmic reticulum calcium ATPase pump activity /SR Ca2+ transport is the major control mechanism for glucose transport, independently of insulin. In addition, our data showed that increased sarcoplasmic reticulum calcium ATPase pump activity restores cardiac glucose transport in insulin-deficient state and ultimately improves whole body glucose homeostasis during diabetes. Furthermore, our results suggesting that SR Ca2+ handling regulates GLUT translocation in part through a Ca2+/calmodulin/AS160 pathway provide valuable mechanistic insights into the regulation of glucose transport in the diabetic heart, which could ultimately lead to the discovery of urgently needed novel therapeutic targets for the treatment or prevention of diabetic cardiomyopathy.

 Along with a few recent studies in liver tissue, this research project helps to set the stage for the groundbreaking concept of linking upregulation of the sarcoplasmic reticulum calcium ATPase pump (which is present in all living organisms) as a therapeutic target not only to rescue muscle function but also to restore glucose metabolism during diabetes.

 

Journal Reference

Waller AP1, Kalyanasundaram A2, Hayes S1, Periasamy M3, Lacombe VA4.

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

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: [email protected]

 

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 sarcoplasmic reticulum calcium ATPase 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 sarcoplasmic reticulum calcium ATPase 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 sarcoplasmic reticulum calcium ATPase 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 sarcoplasmic reticulum calcium ATPase pump in the heart as a potential therapeutic target to improve glucose metabolism during diabetes.

Copyright © 2015 Elsevier B.V. All rights reserved.

Go To PubMed