Development of the strategy to improve sarcopenia in streptozotocin-treated mice by modulation of amino acids in the white muscle.

• Project/Area Number: 21K08583
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Keio University
• Principal Investigator: Miyashita Kazutoshi 慶應義塾大学, 医学部(信濃町), 講師(非常勤) (50378759)
• Co-Investigator(Kenkyū-buntansha): 久保 亜紀子 神戸大学, 医学研究科, 特命講師 (50455573) ; 木内 謙一郎 慶應義塾大学, 医学部(信濃町), 講師 (50528578)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2023: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000); Fiscal Year 2022: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2021: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: サルコペニア / BCAA / ミトコンドリア / エピゲノム / ヒストンアセチル化 / 間欠絶食 / 身体能力 / アミノ酸 / 糖尿病 / ストレプトゾトシン / 質量分析イメージング

Outline of Research at the Start

筋肉が不足した状態であるサルコペニアが, 肥満と同様, 心血管病の発症を予測することから, 医療・介護の広い分野でサルコペニアの重要性が注目されている. 糖尿病では, インスリン作用の不足から, サルコペニアが進行して, 患者の生活の質が低下する. 我々は, インスリン不足に伴う白筋特異的なアミノ酸代謝変容を見出し, その補正により画期的なサルコペニア治療が実現する可能性を着想した. 本研究ではストレプトゾトシン投与1型糖尿病モデルマウスを用いて, 糖尿病に伴う骨格筋の代謝変容を明らかにし, その補正によるサルコペニア治療の開発を目指す.

Outline of Final Research Achievements

Sarcopenia predicts and is associated with the onset of cardiovascular disease, the importance of sarcopenia prevention is attracting attention in a wide range of medical and nursing care fields. Since the mechanism has not been fully elucidated at least from a metabolic perspective, the present study analyzed the skeletal muscle of type 1 diabetes model mice with streptozotocine using imaging mass spectrometry. In addition, in the skeletal muscle of mice subjected to intermittent fasting, we analyzed the epigenome of the fatty acid oxidation gene cluster. As a result, we found that BCAA accumulation in the skeletal muscle may be involved in sarcopenia that is associated with type 1 diabetes. Histone acetylation in skeletal muscle mitochondria-related genes may be involved in improving endurance associated with intermittent fasting

Academic Significance and Societal Importance of the Research Achievements

1型糖尿病に伴うサルコペニアの改善に, 骨格筋BCAA代謝変容の修正が有用である可能性が示唆された.

Research Products

• [Journal Article] Intermittent Fasting Sustainably Improves Glucose Tolerance in Normal Weight Male Mice Through Histone Hyperacetylation (2023)
  • Author(s): Endo Sho、Uto Asuka、Miyashita Kazutoshi、Sato Masaaki、Inoue Hiroyuki、Fujii Kentaro、Hagiwara Aika、Ryuzaki Masaki、Oshida Takuma、Kinouchi Kenichiro、Itoh Hiroshi
  • Journal Title: Journal of the Endocrine Society Volume: 7 Issue: 7
  • DOI: 10.1210/jendso/bvad082
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Intestinal Epithelial NAD+ Biosynthesis Regulates GLP-1 Production and Postprandial Glucose Metabolism in Mice. (2022)
  • Author(s): Nagahisa T, Yamaguchi S, Kosugi S, Homma K, Miyashita K, Irie J, Yoshino J, Itoh H.
  • Journal Title: Endocrinology Volume: 163 Issue: 6
  • DOI: 10.1210/endocr/bqac065
  • Peer Reviewed
• [Journal Article] Home-Based Exercise Program Ameliorates Renal Function Decline in Patients With CKD Stage 4. (2022)
  • Author(s): Adachi K, Uchiyama K, Muraoka K, Nakayama T, Yasuda M, Miyashita K, Tokuyama H, Wakino S, Itoh H.
  • Journal Title: Kidney Int Rep. Volume: 12 Issue: 4 Pages: 809-903
  • DOI: 10.1016/j.ekir.2022.01.006
  • Peer Reviewed / Open Access