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Ca2+-Independent Alterations in Diastolic Sarcomere Length and Relaxation Kinetics in a Mouse Model of Lipotoxic Diabetic Cardiomyopathy

Abstract : Previous studies demonstrated increased fatty acid uptake and metabolism in MHC-FATP transgenic mice that overexpress fatty acid transport protein (FATP)1 in the heart under the control of the ␣-myosin heavy chain (␣-MHC) promoter. Doppler tissue imaging and hemodynamic measurements revealed diastolic dysfunction, in the absence of changes in systolic function. The experiments here directly test the hypothesis that the diastolic dysfunction in MHC-FATP mice reflects impaired ventricular myocyte contractile function. In vitro imaging of isolated adult MHC-FATP ventricular myocytes revealed that mean diastolic sarcomere length is significantly (PϽ0.01) shorter than in wild-type (WT) cells (1.79Ϯ0.01 versus 1.84Ϯ0.01 m). In addition, the relaxation rate (dL/dt) is significantly (PϽ0.05) slower in MHC-FATP than WT myocytes (1.58Ϯ0.09 versus 1.92Ϯ0.13 m/s), whereas both fractional shortening and contraction rates are not different. Application of 40 mmol/L 2,3-butadionemonoxime (a nonspecific ATPase inhibitor that relaxes actin-myosin interactions) increased diastolic sarcomere length in both WT and MHC-FATP myocytes to the same length, suggesting that MHC-FATP myocytes are partially activated at rest. Direct measurements of intracellular Ca 2ϩ revealed that diastolic [Ca 2ϩ ] i is unchanged in MHC-FATP myocytes and the rate of calcium removal is unexpectedly faster in MHC-FATP than WT myocytes. Moreover, diastolic sarcomere length in MHC-FATP and WT myocytes was unaffected by removal of extracellular Ca 2ϩ or by buffering of intracellular Ca 2ϩ with the Ca 2ϩ chelator BAPTA (100 mol/L), indicating that elevated intracellular Ca 2ϩ does not underlie impaired diastolic function in MHC-FATP ventricular myocytes. Functional assessment of skinned myocytes, however, revealed that myofilament Ca 2ϩ sensitivity is markedly increased in MHC-FATP, compared with WT, ventricular cells. In addition, biochemical experiments demonstrated increased expression of the ␤-MHC isoform in MHC-FATP, compared with WT ventricles, which likely contributes to the slower relaxation rate observed in MHC-FATP myocytes. Collectively, these data demonstrate that derangements in lipid metabolism in MHC-FATP ventricles, which are similar to those observed in the diabetic heart, result in impaired diastolic function that primarily reflects changes in myofilament function, rather than altered Ca 2ϩ cycling. (Circ Res. 2009;104:95-103.) Key Words: metabolism Ⅲ diabetes Ⅲ myofilaments Ⅲ remodeling M ounting evidence indicates that cardiac metabolism and disease are intimately related. In this regard, altered energy metabolism is a prominent feature of and, in some instances, may cause heart failure. 1,2 It is also now well recognized that patients with diabetes mellitus have an increased risk of cardiac disease that is independent of the presence of secondary risk factors such as coronary artery disease. 2 These observations suggest that derangements of cardiac metabolism have a direct consequence on cardiac function. The molecular mechanisms potentially linking alterations in metabolism with cardiac pathology are numerous , 2 although poorly understood. The ATP generated in the myocardium that supports cell and organ function, including contraction, is derived largely from 2 metabolic pathways: fatty acid oxidation and glycol-ysis. Under normal conditions, Ϸ60% of the ATP is produced by fatty acid oxidation, with the remainder resulting from the glycolytic metabolism of glucose. Dramatic shifts in this distribution can occur during disease. For example, up to 90% to 100% of the ATP produced in the diabetic myocardium is Original
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Thomas Flagg, Olivier Cazorla, Maria S. Remedi, Todd E. Haim, Michael A. Tones, et al.. Ca2+-Independent Alterations in Diastolic Sarcomere Length and Relaxation Kinetics in a Mouse Model of Lipotoxic Diabetic Cardiomyopathy. Circulation Research, American Heart Association, 2008, 104 (1), pp.95 - 103. ⟨10.1161/CIRCRESAHA.108.186809⟩. ⟨hal-01824362⟩

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