The Sarcoplasmic Reticulum Calcium ATPase Pump Is a Major Regulator of Whole–Body Glucose Metabolism

Abstract

The heart is a very active metabolic organ which exerts endocrine effects by secreting natriuretic peptides. However, its role in the regulation of whole-body metabolism has received scarce attention. Therefore, we hypothesized that cardiac-specific overexpression of the sarcoplasmic reticulum calcium ATPase (SERCA) pump, which tightly regulates cytosolic calcium, modulates whole-body glucose homeostasis during healthy and diabetic states. Diabetes was induced by streptozotocin injections in wild type (WT) and transgenic (TG) mice overexpressing the SERCA pump in the heart (n=4-10/group). Translocation of glucose transporters (GLUTs) was measured in insulin-sensitive tissues using a photolabeled biotinylation assay. The cardiac secretome function was analyzed by mass spectrometry. We reported that blood glucose concentration was lower in diabetic TG mice compared to diabetic WT mice (p=0.023). Cell surface GLUT-4 and -8 protein content was downregulated in the heart of WT diabetic vs. healthy mice (by 56% and 71%, p=0.01 and p<0.001, respectively), which was rescued in TG diabetic mice. In addition, diabetes induced a downregulation of cell surface GLUT4 trafficking in skeletal muscle, and white and brown adipose tissue of WT mice (by 79%, 68% and 74%, respectively, P<0.05), which was restored in TG diabetic mice. We further identified 28 and 32 candidate proteins that have a high probability (i.e., > 95%) of being secreted by the ventricle and atria of TG mice, respectively. Of these, 13 and 10 potentially secreted proteins by the atria and ventricle, respectively, were involved in metabolic processes. In conclusion, these data suggest that cardiac-specific SERCA overexpression rescued hyperglycemia by improving glucose transport in insulin-sensitive tissues of diabetic TG mice. Insights gained from this study could identify the SERCA pump and its secreted proteins as novel pharmacological targets to regulate glucose homeostasis in diabetic patients. Disclosure Z. Maria: None. A. Campolo: None. S. Shoop Gray: None. S. Hartson: None. V. Lacombe: None.