IMPACT OF TREATMENT OF OBESE AND DIBABETIC MICE WITH A NOVEL AMINOSTEROL ON SYSTEMIC METABOLIC HOMEOSTASIS AND MYOCARDIAL MITOCHONDRIAL FUNCTION.

Abstract

Background Cardiovascular disease is the main cause of mortality in diabetes and cardiac dysfunction is due in part to altered myocardial substrate use, occurring in part because of mitochondrial dysfunction and mitochondrial uncoupling. A novel aminosterol, MSI-1436, was recently administered to mouse models of obesity. Short-term treatment resulted in a dramatic reversal of many metabolic disturbances that characterize diabetes. We hypothesized that MSI-1436 would also reverse mitochondrial dysfunction in diabetes. Results Treatment with MSI-1436 resulted in a significant reduction in BW in ob/ob mice compared with ob/ob mice treated with the metabolically inactive control sterol squalamine (SQ). Treatment with MSI-1436 also normalized glucose tolerance in ob/ob mice. State 3 respirations from SQ treated ob/ob hearts were increased and ATP synthesis and ATP/O ratios were decreased compared with WT mice. MSI-1436 treated hearts from ob/ob mice had decreased state 3 respirations compared with SQ treated ob/ob mice, and ATP production decreased further. The mitochondria remained uncoupled as evidenced by reduced ATP/O ratios. Discussion/Conclusions Treatment with MSI-1436 resulted in a significant reduction in BW and normalization of glucose tolerance. However, it was ineffective in reversing mitochondrial dysfunction and uncoupling in cardiac muscle. It may be possible that MSI-1436 could be toxic to these mitochondria or ob/ob hearts may have chronically adapted to use FAs as their primary substrate and are unable to efficiently respond to such an acute treatment. Longer-duration studies will need to be undertaken to test this hypothesis.