Pathogenic mechanism of sarcopenia with diabetes mellitus from the viewpoint of neuromuscular junctions

• Project/Area Number: 18K07412
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52010:General internal medicine-related
• Research Institution: Osaka University
• Principal Investigator: Kurinami Hitomi 大阪大学, 医学系研究科, 招へい教員 (10638555)
• Co-Investigator(Kenkyū-buntansha): 杉本 研 大阪大学, 医学系研究科, 招へい教授 (20437403)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: サルコペニア / 糖尿病 / 神経筋接合部 / CAF（C末アグリンフラグメント） / AGEｓ（終末糖化産物） / ユビキチンプロテアソーム

Outline of Final Research Achievements

Diabetes mellitus is a well-established risk factor for sarcopenia. At first, we focused on the protein associated with neuromuscular junction in diabetes. Our hypothesis was that C-terminal Agrin fragment(CAF), which is a marker of muscle wasting , increased in diabetics. So we measured serum CAF in diabetic animal model. However, there was no differences between control group and hyperglycemic group. We also investigated the expression of ubiquitin proteasome genes in this animal model and found that the expression of Atrogin1 and MurF1 increased in the diabetic group via AGEs/RAGE. These results suggest that muscle protein degradation is caused by activation of ubiquitin proteasome genes in diabetic model.

Academic Significance and Societal Importance of the Research Achievements

超高齢社会において健康寿命の延長が急務であるが、高齢者の活動性の低下を招く要因の一つがサルコペニアであると考えられる。今回の成果により、糖尿病を治療することによってAGEs/RAGEによって引き起こされるユビキチンプロテアソーム系の活性を抑制することとなり結果として骨格筋量減少を抑制できるという可能性が示唆されたと考える。すなわち糖尿病の治療によりサルコペニアの進展を抑制できるということを、そのメカニズムの解明によって証明できつつあるという点で意義があったと考える。