Role of lactate metabolism in the metabolic flexibility of the heart.

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K23992
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0903:Organ-based internal medicine and related fields
• Research Institution: Osaka Metropolitan University (2022); Osaka City University (2019-2021)
• Principal Investigator: Nakagama Yu 大阪公立大学, 大学院医学研究科, 准教授 (60846880)
• Project Period (FY): 2019-08-30 – 2023-03-31
• Keywords: 心臓 / エネルギー代謝 / 乳酸

Outline of Final Research Achievements

It has long been difficult to analyze energy metabolism with high precision in cardiac tissues, which show rapid metabolic turnover. We herein applied our optimized methodology for tissue fixation and metabolite extraction for depicting, with high sensitivity, cardiac lactate metabolism. We performed phenotypic analysis of LDH-deficient mice under multiple cardiac overload conditions and were able to show that LDH-deficient mice have impaired tolerance to increased afterload and/or exercise. Furthermore, we succeeded in depicting that the "hyperreduced state (electron congestion)" of the heart, triggered by impaired lactate metabolism, characterized the metabolic signature of LDH-deficient hearts and played central roles in inducing the cardiac dysfunction. Heart lactate oxidation was stimulating mitochondrial respiration via a concerted NADH recycling reaction with the malate-aspartate shuttle.

Free Research Field

循環器病学

Academic Significance and Societal Importance of the Research Achievements

代謝回転の早い心臓組織においてエネルギー代謝を高精度に解析することは困難であったが、我々は、独自に最適化した試薬投与方法、臓器固定・回収時間、代謝物抽出法により、高感度な心臓メタボローム解析を実現した。これらを、世界に先駆け樹立したLDHアイソフォーム心臓特異的欠失マウスの心臓疾患代謝解析に適用することで、心臓病態を通底する疾患代謝の特徴の一つとして「過還元状態」の存在が示唆された。エネルギー基質としての乳酸が持つ固有の役割が明らかとなり、今後、乳酸代謝を切り口とした病態理解、心筋ミトコンドリア呼吸賦活法の開発への貢献が期待される。