Activation mechanisms of skeletal muscle stem cells during regeneration

2018 Fiscal Year Final Research Report

• Project/Area Number: 16H04793
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Developmental biology
• Research Institution: Kyoto University
• Principal Investigator: Sehara-Fujisawa Atsuko 京都大学, ウイルス・再生医科学研究所, 連携教授 (60209038)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 再生医学 / 細胞・組織 / 発生・分化 / 生体分子 / ゲノム

Outline of Final Research Achievements

We investigated factors stimulating differentiation of skeletal muscle satellite cells (SMSCs), and found that pyruvate, the end product of glycolysis, stimulates their differentiation. Pyruvate antagonizes effects of hypoxia on preferential self-renewal of SMSCs through dephosphorylation or activation of pyruvate dehydrogenase (PDH), which mediates opening of the gateway from glycolysis to tricarboxylic acid (TCA) cycle by producing acetyl coA from pyruvate. PDH kinase 1 is decreased under normoxic conditions, leading to an increase in dephosphorylated PDH. Conditional deletion of PDH in SMSCs affects cell divisions generating myocytes and subsequent myotube formation skeletal muscle regeneration upon injury, and aggravated pathogenesis of dystrophin-deficient mice. Thus, the metabolic flow from glycolysis to TCA cycle mediated by PDH plays a pivotal role in the efficient differentiation of SMSCs, which is critical for the progression of skeletal muscle regeneration.

Free Research Field

発生生物学・細胞生物学

Academic Significance and Societal Importance of the Research Achievements

幹細胞がどのようなメカニズムで活性化され、増殖・分化するのか、という問題については、幹細胞研究が盛んな割にはわかっていない。その中にあって、最も基本的なエネルギー利用の観点から、糖代謝の変化が骨格筋幹細胞の分化に必要ということを、細胞レベル・個体レベルで示すことができ、学術的にも、医学応用的にも、非常に重要な知見を生み出すことができた。