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

• 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
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 心臓 / エネルギー代謝 / 乳酸 / 酸素呼吸 / 嫌気的解糖 / 代謝フラックス / 解糖系 / ミトコンドリア呼吸 / 心筋

Outline of Research at the Start

末梢への循環維持装置である心臓は、いかなる生理的・病的状況においても、血液ポンプとして収縮・拡張を続ける使命を負う。激しい外的環境・内的需要の変化に順応すべく、心臓は「雑食な臓器」として適応しあらゆるエネルギー基質を巧妙に使い分けている。多くの細胞・体内組織にとって、解糖系の最終産物として外部へ排出する対象である「乳酸」も、心臓にとっては重要なエネルギー基質である。本申請では、マウス遺伝子工学的手法と心臓エネルギー代謝解析手法を駆使し、莫大な酸素消費と引き換えにしてまで、他細胞にとっては老廃物に過ぎない乳酸を敢えて積極的に代謝するようになった「心筋の代謝適応戦略」の理解を目指す。

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.

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。

Research Products

• [Int'l Joint Research] 国立ロサレス病院/エルサルバドル国立衛生研究所(エルサルバドル)
• [Journal Article] Cardiomyocyte transcriptomic signatures in response to Trypanosoma cruzi infection underpin Chagas cardiomyopathy progression (2023)
  • Author(s): Candray-Medina KS, Nakagama Y, Ito M, Nakagama S, Tshibangu-Kabamba E, Takeda N, Sugiura Y, Nitahara Y, Michimuko-Nagahara Y, Kaku N, Onizuka Y, Arias CE, Mejia M, Alas K, Pena S, Maejima Y, Komuro I, Nakajima-Shimada J, Kido Y
  • Journal Title: bioRxiv Volume: 2023.02.27 Pages: 530371-530371
  • DOI: 10.1101/2023.02.27.530371
  • Open Access / Int'l Joint Research
• [Journal Article] Towards Deeper Phenotyping of the Dilated Cardiomyopathies in Children ― Where Are We Now, and Where Are We Heading? ― (2021)
  • Author(s): Nakagama Yu、Ito Masamichi
  • Journal Title: Circulation Journal Volume: 86 Issue: 1 Pages: 116-117
  • DOI: 10.1253/circj.CJ-21-0802
  • NAID: 130008132643
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2021-12-24
  • Peer Reviewed / Open Access
• [Journal Article] Poor Myocardial Compaction in a Patient with Recessive <i>MYL2</i> Myopathy (2021)
  • Author(s): Tamamitsu AM, Nakagama Y, Domoto Y, Yoshida K, Ogawa S, Hirono K, Shindo T, Ogawa Y, Nakano K, Asakai H, Hirata Y, Matsui H, Inuzuka R
  • Journal Title: International Heart Journal Volume: 62 Issue: 2 Pages: 445-447
  • DOI: 10.1536/ihj.20-639
  • NAID: 130008007427
  • ISSN: 1349-2365, 1349-3299
  • Year and Date: 2021-03-30
  • Peer Reviewed / Open Access
• [Journal Article] Inflammatory cardiomyopathy of possibly overlapping aetiology: a case posing treatment dilemma and potential association (2021)
  • Author(s): Nakagama Shun、Candray Katherine、Yamamoto Tasuku、Tsugeno Yuta、Nakagama Yu、Kido Yasutoshi、Nitahara Yuko、Maejima Yasuhiro、Sasano Tetsuo
  • Journal Title: ESC Heart Failure Volume: 9 Issue: 1 Pages: 761-765
  • DOI: 10.1002/ehf2.13771
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Therapeutic targeting of mitochondrial ROS ameliorates murine model of volume overload cardiomyopathy. (2019)
  • Author(s): Okamura K, Nakagama Y, Takeda N, Soma K, Sato T, Isagawa T, Kido Y, Sakamoto M, Manabe I, Hirata Y, Komuro I, Ono M
  • Journal Title: Journal of Pharmacological Sciences Volume: 141 Issue: 1 Pages: 56-63
  • DOI: 10.1016/j.jphs.2019.09.005
  • Peer Reviewed / Open Access
• [Journal Article] Noonan syndrome‐associated biallelic LZTR1 mutations cause cardiac hypertrophy and vascular malformations in zebrafish (2019)
  • Author(s): Nakagama Yu、Takeda Norihiko、Ogawa Seishi、Takeda Hiroyuki、Furutani Yoshiyuki、Nakanishi Toshio、Sato Tatsuyuki、Hirata Yoichiro、Oka Akira、Inuzuka Ryo
  • Journal Title: Molecular Genetics & Genomic Medicine Volume: 8 Issue: 3
  • DOI: 10.1002/mgg3.1107
  • Peer Reviewed / Open Access
• [Presentation] In vitro transcriptomic remodeling of cardiomyocytes caused by Trypanosoma cruzi. (2023)
  • Author(s): Katherine Candray-Medina, Yu Nakagama, Shun Nakagama, Masamichi Ito, Yu Michimuko, Evariste Tshibangu-Kabamba, Akira Kaneko, Yasutoshi Kido
  • Organizer: 第92回 日本寄生虫学会大会
• [Presentation] Role of cardiomyocytes as host-parasite interaction sentinels in Chagas disease. (2023)
  • Author(s): 中釜 悠,伊藤 正道,Candray Katherine,中釜 瞬,嶋田 淳子,Arias Carmen-Elena,城戸 康年
  • Organizer: 第126回 日本小児科学会学術集会
• [Presentation] iPS cell-derived cardiomyopathy model as the translational hub for Chagas disease biomarker discovery: bridging in vitro host-parasite interplay to clinical proof-of-concept. (2023)
  • Author(s): Yu Nakagama, Masamichi Ito, Katherine Candray, Carmen Elena Arias, Susana Pena, Maricela Mejia, Karla Marina Alas, Roberto Leonel Ayala Minero, Yuko Nitahara, Yoko Onizuka, Junko Shimada, Rosa Maria Guerrero, William Mejia, Yasutoshi Kido
  • Organizer: Pediatric Academic Societies (PAS) Meeting 2023
  • Int'l Joint Research
• [Presentation] Induced pluripotent stem cell-derived Chagas disease model highlights the role of cardiomyocytes as sentinels of the host-parasite interaction. (2022)
  • Author(s): Nakagama Y, Candray K, Nitahara Y, Takeda N, Shimada J, Arias CE, Kaneko A, Komuro I, Kido Y.
  • Organizer: 55th Annual Meeting of the Association for European Paediatric and Congenital Cardiology
  • Int'l Joint Research
• [Presentation] Induced Pluripotent Stem Cell-derived Chagas Disease Model Highlights The Role Of Cardiomyocytes As Sentinels Of The Host-parasite Interaction. (2022)
  • Author(s): Y. Nakagama, M. Ito, K. Candray, Y. Nitahara, Y. Kido
  • Organizer: ASM Microbe 2022
  • Int'l Joint Research
• [Presentation] RASopathy関連心筋症の細胞レベル表現型の理解 (2022)
  • Author(s): 中釜悠
  • Organizer: 第57回 日本小児循環器学会学術集会
  • Invited
• [Presentation] Symptomatic AV block encountered in the Latin American context: rethinking the etiological diagnosis in the globalized era (2022)
  • Author(s): Shun Nakagama, Katherine Candray, Tasuku Yamamoto, Yu Nakagama, Yasutoshi Kido, Yasuhiro Maejima, Tetsuo Sasano
  • Organizer: 第86回日本循環器学会学術集会
• [Presentation] シャーガス心筋症in vitroモデリングによる病態理解 (2022)
  • Author(s): 中釜悠、Katherine Candray、伊藤正道、仁田原裕子、金子明、城戸康年
  • Organizer: 第90回日本寄生虫学会
• [Presentation] シャーガス慢性心筋炎の病態形成機構 (2020)
  • Author(s): 中釜悠
  • Organizer: 第56回日本小児循環器学会総会・学術集会
• [Presentation] Lactate as a fuel for the mammalian heart (2019)
  • Author(s): Nakagama Y, Takeda N, Kido Y, Sato T, Inuzuka R, Komuro I
  • Organizer: 第92回日本生化学会大会