Impaired SERCA function contributes to cardiomyocyte dysfunction in insulin resistant rats

• Published in: Journal of molecular and cellular cardiology 2005-08, Vol.39 (2), p.297-307
• Main Authors: Wold, Loren E., Dutta, Kaushik, Mason, Meredith M., Ren, Jun, Cala, Steven E., Schwanke, Mary L., Davidoff, Amy J.
• Format: Article
• Language: English
• Subjects: Abnormal Ca 2+ regulation; Animals; Caffeine - pharmacology; Calcium Signaling - drug effects; Calcium-Transporting ATPases - metabolism; Cardiomyopathy; Insulin Resistance - physiology; Ion Exchange; Male; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - enzymology; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; NCX; Rats; Rats, Wistar; Sarcoplasmic Reticulum - drug effects; Sarcoplasmic Reticulum - metabolism; Sarcoplasmic Reticulum Calcium-Transporting ATPases; SERCA; Starch - pharmacology; Sucrose - pharmacology; Type 2 diabetes
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2005.03.014

Ventricular dysfunction in type 2 diabetic patients is becoming apparent early after diagnosis of diabetes, but the cellular mechanisms contributing to this dysfunction are not well established. Our group has recently identified cardiomyocyte dysfunction in diet-induced insulin resistant rats that have not developed type 2 diabetes. The present investigation was designed to determine cellular mechanisms contributing to slowed cardiomyocyte relaxation in sucrose (SU)-fed rats. SU-feeding was used to induce whole-body insulin resistance. After 9–12 weeks on diet, isolated ventricular myocyte shortening/relengthening were slower in SU-fed adult male Wistar rats (42–63%) compared to starch (ST)-fed controls. Cytosolic Ca 2+ removal attributable to Na +/Ca 2+ exchange (NCX) and to sarco(endo)plasmic reticulum Ca 2+-ATPase (SERCA) was evaluated with fluo-3/AM. Caffeine-releasable Ca 2+ and cytosolic Ca 2+ clearing through NCX were normal, whereas Ca 2+ uptake by SERCA was significantly slower in SU myocytes (330 ± 29 ms) compared to ST cells (253 ± 16 ms). Protein levels for SERCA, NCX and phospholamban were not affected by SU-feeding. Manipulating intracellular Ca 2+ with various positive inotropic interventions (e.g. post-rest potentiation, isoproterenol) and changes in stimulus frequency demonstrated that mechanical properties can be improved in subsets of myocytes. Thus, we conclude that impaired SERCA activity (with normal protein content) contributes to cardiomyocyte dysfunction in insulin resistant animals, whereas NCX function and expression are normal. These results suggest that subtle changes in Ca 2+ regulation which occur prior to overt ventricular dysfunction/failure, may be common to early stages of a number of disorders involving insulin resistance (e.g. diabetes, obesity, syndrome X and hypertension).