mTOR-mediated calcium transients affect cardiac function in ex vivo ischemia–reperfusion injury

Briana K. Shimada, Naaiko Yorichika, Jason K. Higa, Yuichi Baba, Motoi Kobayashi, Toshinori Aoyagi, Tomohiro Suhara, Takashi Matsui

Research output: Contribution to journalArticlepeer-review

Abstract

The mechanistic target of rapamycin (mTOR) is a key mediator of energy metabolism, cell growth, and survival. While previous studies using transgenic mice with cardiac-specific overexpression of mTOR (mTOR-Tg) demonstrated the protective effects of cardiac mTOR against ischemia–reperfusion (I/R) injury in both ex vivo and in vivo models, the mechanisms underlying the role of cardiac mTOR in cardiac function following I/R injury are not well-understood. Torin1, a pharmacological inhibitor of mTOR complex (mTORC) 1 and mTORC2, significantly decreased functional recovery of LV developed pressure in ex vivo I/R models (p < 0.05). To confirm the role of mTOR complexes in I/R injury, we generated cardiac-specific mTOR-knockout (CKO) mice. In contrast to the effects of Torin1, CKO hearts recovered better after I/R injury than control hearts (p < 0.05). Interestingly, the CKO hearts had exhibited irregular contractions during the reperfusion phase. Calcium is a major factor in Excitation-Contraction (EC) coupling via Sarcoplasmic Reticulum (SR) calcium release. Calcium is also key in opening the mitochondrial permeability transition pore (mPTP) and cell death following I/R injury. Caffeine-induced SR calcium release in isolated CMs showed that total SR calcium content was lower in CKO than in control CMs. Western blotting showed that a significant amount of mTOR localizes to the SR/mitochondria and that GSK3-β phosphorylation, a key factor in SR calcium mobilization, was decreased. These findings suggest that cardiac mTOR located to the SR/mitochondria plays a vital role in EC coupling and cell survival in I/R injury.

Original languageEnglish
Article numbere14807
JournalPhysiological Reports
Volume9
Issue number6
DOIs
Publication statusPublished - 2021 Mar

Keywords

  • calcium
  • cardiomyocyte
  • ischemia–reperfusion
  • mTOR

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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