Alisporivir Treatment Alleviates Mitochondrial Dysfunction in the Skeletal Muscles of C57BL/6NCrl Mice with High-Fat Diet/Streptozotocin-Induced Diabetes Mellitus

Abstract

Diabetes mellitus is a systemic metabolic disorder associated with mitochondrial dysfunction, with mitochondrial permeability transition (MPT) pore opening being recognized as one of its pathogenic mechanisms. Alisporivir has been recently identified as a non-immunosuppressive analogue of the MPT pore blocker cyclosporin A and has broad therapeutic potential. The purpose of the present work was to study the effect of alisporivir (2.5 mg/kg/day i.p.) on the ultrastructure and functions of the skeletal muscle mitochondria of mice with diabetes mellitus induced by a high-fat diet combined with streptozotocin injections. The glucose tolerance tests indicated that alisporivir increased the rate of glucose utilization in diabetic mice. An electron microscopy analysis showed that alisporivir prevented diabetes-induced changes in the ultrastructure and content of the mitochondria in myocytes. In diabetes, the ADP-stimulated respiration, respiratory control, and ADP/O ratios and the level of ATP synthase in the mitochondria decreased, whereas alisporivir treatment restored these indicators. Alisporivir eliminated diabetes-induced increases in mitochondrial lipid peroxidation products. Diabetic mice showed decreased mRNA levels of Atp5f1a, Ant1, and Ppif and increased levels of Ant2 in the skeletal muscles. The skeletal muscle mitochondria of diabetic animals were sensitized to the MPT pore opening. Alisporivir normalized the expression level of Ant2 and mitochondrial susceptibility to the MPT pore opening. In parallel, the levels of Mfn2 and Drp1 also returned to control values, suggesting a normalization of mitochondrial dynamics. These findings suggest that the targeting of the MPT pore opening by alisporivir is a therapeutic approach to prevent the development of mitochondrial dysfunction and associated oxidative stress in the skeletal muscles in diabetes.

Alisporivir Normalizes Mitochondrial Function of Primary Mouse Lung Endothelial Cells Under Conditions of Hyperglycemia

“…In the previous studies, we have shown that the long-term (3 weeks) administration of the MPT pore inhibitor alisporivir (a non-immunosuppressive analogue of cyclosporine A) to the mice with induced diabetes leads to alleviation of the eff ects of diabetic mitochondrial dysfunction in the skeletal and cardiac muscles. Moreover, alisporivir increases the rate of glucose utilization from the blood of diabetic animals during the glucose tolerance test [25,26]. In the present work, we continue to study the eff ect of alisporivir on mitochondrial dysfunction induced by hyperglycemia.…”

“…Alisporivir suppresses development of mitochondrial dysfunction in the mouse lung endotheliocytes under hyperglycemia. In the previous studies, we have shown that in vivo administration of alisporivir to the mice with type II diabetes normalizes functioning of heart and skeletal muscle mitochondria [25,26]. In this work, we evaluated the eff ect of alisporivir on mitochondria functioning in the primary culture of mouse lung endotheliocytes un- der conditions of hyperglycemia.…”

“…A number of studies have shown that the mitochondria-targeted gene or pharmacological therapy restores structural and functional parameters of mitochondria, reduces complications of diabetes mellitus, including increase in the insulin sensitivity of tissues and organs, and has a hypoglycemic eff ect [23,25,37]. In the previous studies, we have shown that the long-term treatment of diabetic mice with alisporivir (an MPT pore inhibitor) leads to both decrease in the mitochondrial dysfunction in skeletal and cardiac muscles and increase in the rate of glucose utilization from the blood during a glucose tolerance test [25]. In the present work, we examined intracellular mechanisms that may underlie the protective eff ect of alisporivir against the high glucose-mediated damage in the mouse lung endotheliocytes.…”

“…One could debate whether the lack of adaptive response such as mitophagy is benefi cial during the development of diabetes mellitus, but our previous studies suggest that alisporivir has a therapeutic eff ect during long-term administration to diabetic animals [25,26]. Indeed, we have previously demonstrated that the heart of diabetic mice exhibits decrease in the expression of the Pink1 and Parkin genes, and long-term (3 weeks) administration of alisporivir to diabetic animals leads to normalization of the expression of these genes [26].…”

Mitophagy and mitochondrial dynamics in type 2 diabetes mellitus treatment

“…Additionally, in vivo study, C57BL/6NCrl mice fed with high-fat diet and induction with streptozotocin to develop a DM like mice. The DM like mice demonstrated that increased the protein expression of fission gene (DRP1) and decreased the protein expression of fusion genes MNF2 and OPA1), as well as PPARGc1a (key gene regulator in mitochondrial biogenesis) [ 43 ].…”