PS-B12-8: ANGIOTENSIN II TYPE I RECEPTOR SIGNAL REGULATES MITOCHONDRIAL DYNAMICS, CAUSING MUSCULAR MITOCHONDRIAL DYSFUNCTION AND SARCOPENIA UNDER METABOLIC STRESS

Abstract

Introduction: Metabolic stress, such as oxidized low density lipoprotein (ox-LDL) and advanced glycation end products (AGE) cause atherosclerotic cardiovascular diseases through dysfunction of mitochondria, which undergo quality control by mitochondrial dynamics, fission and fusion. Mitochondria also plays a crucial role in regulating muscular function, and its dysfunction leads to sarcopenia. This study aims to clarify whether and how mitochondrial dynamics are involved in the development of sarcopenia under metabolic stress. Methods: We used human skeletal muscle cells (HSMC) in in vitro experiments and C57BL6 (WT), apolipoprotein E (ApoE) deficient and the double knockout of ApoE and AT1R (DKO) mice in in vivo experiments. Results: Administration of either ox-LDL or AGE to HSMC induced mitochondrial fission through activation of fission factor, Drp1, decreased mitochondrial membrane potential assessed by JC-1 staining and increased reactive oxygen species assessed by Mito-sox Red staining and apoptosis, which were restored by Drp1-specific inhibitor, mdivi-1. Inhibition of angiotensin II type 1 receptor (AT1R) by AT1R blocker also ameliorated excessive mitochondrial fission, its function and oxidative stress induced by either ox-LDL or AGE in HSMC. These results suggest that metabolic stress induces mitochondrial fission and its dysfunction, which may cause sarcopenia. Muscular strength and the ratio of muscle weight to tibia length were lower in ApoE than those in WT. The number of fused mitochondria and mitochondrial function were lower and oxidative stress and the number of apoptotic cell were higher in ApoE KO than those of WT. Muscle strength, the ratio of muscle weight to tibia length, the number of fused mitochondria and its function were higher and the number of apoptotic cell were lower in DKO than those in ApoE KO mice. Taken together, these results suggest that either ox-LDL or AGE causes sarcopenia through AT1R signal-dependent mitochondrial fission and subsequent mitochondrial dysfunction. Conclusion: Either ox-LDL or AGE induces mitochondrial dysfunction through AT1R signal-regulating mitochondrial fission, which causes sarcopenia. Inhibition of AT1R signal may be a potential therapeutic strategy to avoid development of sarcopenia in patients with life style related diseases, such as dyslipidemia and diabetics.