Mitochondrial ATP Biosynthesis Is Negatively Associated with FFA in Cardiac and Skeletal Muscle During the...

Many factors related to obesity can impact how mitochondria produce ATP, such as the uncoupling of oxidative phosphorylation (OXPHOS) caused by proton leaks from built-up free fatty acids (FFA), the increased levels of uncoupling proteins (UCPs), and changes in the levels of ATPase inhibitory protein factors 1 (IF1). Therefore, the present study aimed to assess the rate of ATP synthesis in mitochondria isolated from skeletal and cardiac muscle from animal models of sucrose diet-induced obesity at different time periods. Short periods of sucrose intake (6 and 12 weeks) are sufficient to induce fat accumulation, hypertriglyceridemia, and high plasma FFA. However, a significant decline in the ATP synthesis rate starts to be obvious in mitochondria from skeletal muscle after 24 weeks of sucrose consumption. This impairment of ATP synthesis is associated with increased FFA in skeletal muscle homogenate. ATP synthesis rates in both skeletal and cardiac muscle were found to be sensitive to oleic acid and GDP, a physiological inhibitor of UCPs that has been shown to increase with aging. In addition, a sucrose diet increases the IF1 content in both skeletal and heart muscle, probably to avoid the hydrolytic activity of ATP synthase. In mitochondria from heart muscle, a decrease in the ATP synthesis rate was only observed according to the age in both groups of rats, and it was not affected by sucrose feeding. Our results suggest that the decline of the ATP synthesis rate in mitochondria from skeletal muscle can be due to the accumulation of FFA in skeletal muscle tissue as uncouplers, and the IF1 overexpression induced by the sucrose diet is a response mechanism to avoid the ATP hydrolysis and to save the energy charge reduced by FFA-uncoupling OXPHOS.