Ceylan-Isik, Asli F., Karissa H. LaCour, and Jun Ren. Sex difference in cardiomyocyte function in normal and metallothionein transgenic mice: the effect of diabetes mellitus. J Appl Physiol 100: 1638-1646, 2006. First published January 12, 2006 doi:10.1152/japplphysiol.01273.2005.-Evidence suggests a sex difference in intrinsic physiological and diabetic myocardial contractile function related to antioxidant properties of female ovarian hormones. This study was designed to examine the effect of cardiac overexpression of antioxidant metallothionein on intrinsic and diabetic cardiomyocyte function. Weight-matched wildtype (FVB) and metallothionein transgenic mice of both sexes were made diabetic with streptozotocin (220 mg/kg). Contractile and intracellular Ca 2ϩ properties were evaluated including peak shortening (PS), time to PS, time to 90% relengthening (TR90), maximal velocity of shortening or relengthening (ϮdL/dt), fura-2 fluorescence intensity change, and Ca 2ϩ decay rate. Akt and transcription factor c-Jun levels were evaluated by Western blot. Myocytes from female FVB mice exhibited lower PS, ϮdL/dt, and fura-2 fluorescence intensity change, prolonged time to PS, TR 90, and Ca 2ϩ decay compared with male FVB mice. Interestingly, this sex difference was not present in metallothionein mice. Diabetes depressed PS, ϮdL/dt and caffeineinduced Ca 2ϩ release, as well as prolonged TR90 and Ca 2ϩ decay in male FVB mice, whereas it only reduced PS in female FVB mice. These diabetic dysfunctions were nullified by metallothionein in both sexes. Females displayed elevated Akt phosphorylation and reduced c-Jun phosphorylation. Diabetes dampened Akt phosphorylation in male FVB mice and enhanced c-Jun in both sexes. Diabetes-induced alterations in Akt phosphorylation and c-Jun were abolished by metallothionein. The sex difference in Akt phosphorylation but not c-Jun levels was reversed by metallothionein. These data indicate that antioxidant capacity plays an important role in sex differences in both intrinsic and diabetic cardiomyocyte contractile properties possibly related to phosphorylation of Akt and c-Jun. myocyte shortening; Akt; c-Jun DIABETIC CARDIOMYOPATHY, a unique deterioration of myocardial function found in the diabetic population, is a prominent form of diabetic complications independent of macro-and microvascular complications of diabetes mellitus (9, 23). It is characterized by impaired ventricular contraction, relaxation, and wall compliance (9,23,24,41). Both clinical and experimental evidence has revealed impaired intracellular Ca 2ϩ homeostasis, reduced contractility, prolonged duration of contraction and relaxation associated with enhanced free radical accumulation, and oxidative damage in the heart (7,9,11,12,22,24,31,32,41). Interestingly, a "female advantage" exists in premenopausal women with regard to the propensity and severity of diabetic heart diseases (23, 35, 36). Sex differences in myocardial and cardiomyocyte contractile function have long been established, mainly manifested as differe...