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mTORC1 and mTORC2 play different roles in regulating cardiomyocyte differentiation from embryonic stem cells

Bei Zheng1, Jiadan Wang, Leilei Tang

  • 1Institute of Pharmacology and Toxicology, Zhejiang University, Hangzhou, China.

The International Journal of Developmental Biology
|March 14, 2017
PubMed

Insights

Mammalian target of rapamycin complex 2 (mTORC2) activation is critical for cardiomyocyte differentiation from mouse embryonic stem cells. mTORC1 inhibition enhances this process by upregulating mTORC2 signaling.

Area of Science:

  • Cell Biology
  • Developmental Biology
  • Stem Cell Research

Background:

  • Mammalian target of rapamycin (mTOR) signaling pathways, specifically mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), are vital for cellular survival and growth.
  • The precise roles of mTORC1 and mTORC2 in regulating cardiomyocyte differentiation from mouse embryonic stem cells (mESCs) remain largely undefined.

Purpose of the Study:

  • To elucidate the distinct functions of mTORC1 and mTORC2 in directing cardiomyocyte differentiation from mESCs.
  • To investigate the interplay between mTORC1 and mTORC2 during this differentiation process.

Main Methods:

  • Knockdown experiments targeting Raptor (mTORC1 component) and Rictor (mTORC2 component) in mESCs.
  • Quantitative analysis of cardiomyocyte differentiation markers and myofilament organization.
  • Assessment of protein phosphorylation levels, specifically Rictor phosphorylation at Thr1135.

Main Results:

  • Raptor ablation significantly enhanced cardiomyocyte differentiation, increasing the number of cells with organized myofilaments and upregulating cardiac markers (brachyury, Nkx2.5, α-Actinin).
  • Rictor loss impaired cardiomyocyte differentiation, and dual ablation of Raptor and Rictor reduced cardiomyocyte numbers.
  • Knockdown of Raptor/mTORC1 led to decreased Rictor phosphorylation, consequently activating Rictor/mTORC2 signaling and promoting mESC differentiation into cardiomyocytes.

Conclusions:

  • mTORC1 and mTORC2 exhibit opposing roles in mESC-derived cardiomyocyte differentiation.
  • Activation of Rictor/mTORC2 is essential for facilitating cardiomyocyte differentiation.
  • Targeting mTORC2 presents a potential strategy for regulating myocardial differentiation from stem cells.

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