Sarcoplasmic Ca2+ release is prolonged in nonfailing myocardium of diabetic patients

Abstract

Background Asymptomatic diabetic patients have a high incidence of clinically unrecognized left ventricular dysfunction with an abnormal cardiac response to exercise. We, therefore, examined subclinical defects in the contraction-relaxation cycle and intracellular Ca(2+) regulation in myocardium of asymptomatic type 2 diabetic patients. Methods Alterations in the dynamics of the intracellular Ca(2+) transient and contractility were recorded in right atrial myocardium of type 2 diabetic patients and non-diabetic control tissue loaded with fura-2. In order to gain an insight into mechanisms underlying the altered Ca(2+) handling in diabetic myocardium levels of mRNA, protein expression and phosphorylation of key proteins in sarcoplasmic Ca(2+) handling were determined. Results In isolated atrial trabeculae of diabetic myocardium the rise of systolic Ca(2+) was significantly prolonged, but relaxation of the Ca(2+) transient was unaltered compared to control tissue. Accordingly, the levels of expression of mRNA and protein of the Ca(2+) release channel (RyR2) of the sarcoplasmic reticulum were reduced by 68 and 22%, respectively. Endogenous phosphorylation of RyR2 by protein kinases C, however, was increased by 31% in diabetic myocardium, as assessed by the back-phosphorylation technique. Levels of expression of SERCA2 and phospholamban were unaltered between both groups. Conclusions Intracellular Ca(2+) release is prolonged in non-failing myocardium of type 2 diabetic patients and this may be primarily due to a decreased expression of RyR2. This defective Ca(2+) release may represent an early stage of ventricular dysfunction in type 2 diabetes and would favor the abnormal response to exercise frequently observed in asymptomatic diabetic patients.

In vivo imaging of intracellular Ca2+ after muscle contractions and direct Ca2+ injection in rat skeletal muscle in diabetes

“…7). In cardiomyocytes, previous studies indicated that there was a lower density of RyR and a quantitative relationship between the altered contraction-relaxation cycle and reduced Ca 2ϩ release (31,42,52). In fact, Venetucci et al (54) reported a lower transient amplitude of [Ca 2ϩ ] i consistent with a decreased SR calcium content.…”

Endoplasmic-Reticulum Calcium Depletion and Disease

“…The changes in SR Ca 2þ handling depend on the type of diabetes, the experimental model, the degree of hyperglycemia, and the extent of disease progression. SR function is already abnormal at an insulin-resistant stage before the manifestation of overt type-2 diabetes (Dutta et al 2002;Wold et al 2005;Vasanji et al 2006;Reuter et al 2008).…”

Effect of zinc supplementation on lipid peroxidation and lactate levels in rats with diabetes induced by streptozotocin and subjected to acute swimming exercise

“…Impairments of calcium secretion in diabetes lead to dysfunctions in muscle contractions (38), which in turn, caused faster onset of muscle exhaustion. As a matter of fact, the fi ndings of increased lactate levels found after exercise in diabetes (39) or signifi cant increases in lactate levels resulting from high-intensity exercise in diabetics (40) prove that muscle exhaustion occurs earlier in diabetes-exercise correlation.…”