Redox-Dependent Differential Optimization of Contractile Work in Cardiac Muscle from Diabetic Rat under Hyperglycemia

Abstract

Type 2 diabetes mellitus (T2DM) is characterized by obesity, hyperglycemia and insulin resistance; these traits are recapitulated by the Zucker Diabetic Fatty (ZDF) rat model. Although fatty acid oxidation is known to be augmented in the heart, it is unclear how substrate fuel selection and redox behavior affect optimization of cardiac work output in T2DM. We studied the mechanical, and energetics/redox behavior of heart trabeculae from ZDF rats and their lean controls perfused with either normal (euglycemia, EG, 5mM) or high glucose (HG, 30mM), in the absence or presence of Palmitate (Palm). Contractile performance, measured as developed force and area under the muscle tension curve (contractile work), increased with frequency, as did oxygen consumption rate (VO2). The ratio of contractile work over VO2 was defined as an index of the energy yield for contractile work (Ycw). Unlike in lean animals, ZDF heart trabeculae showed a significant increase in Ycw under HG in the presence of Palm. On the contrary, ZDF trabeculae perfused under EG in the presence of Palm exhibited lower Ycw than in lean animals, in agreement with published data. The improved function with Palm under HG was associated with improved redox status in ZDF trabeculae, but not in lean controls. Indeed, MCB fluorescence, an indicator of cellular GSH levels, and the probe of oxidative stress, CM-DCF, revealed more oxidizing redox conditions under HG that could be reverted by the addition of Palm in ZDF trabeculae. In contrast with the behavior under EG, Palm elicited an increased reliance of contractility on glycolysis in conjunction with oxidative phosphorylation under HG in ZDF but not in lean trabeculae. As a result, Palm induces a redox-dependent higher contractile work yield from respiration in muscles from diabetic rat hearts.