Amino acid primed mTOR activity is essential for heart regeneration

Jason W Miklas; Shiri Levy; Peter Hofsteen; Diego Ic Mex; Elisa Clark; Jeanot Muster; Aaron M Robitaille; Gargi Sivaram; Lauren Abell; Jamie M Goodson; Inez Pranoto; Anup Madan; Michael T Chin; Rong Tian; Charles E Murry; Randall T Moon; Yuliang Wang; Hannele Ruohola-Baker

doi:10.1016/j.isci.2021.103574

Amino acid primed mTOR activity is essential for heart regeneration

iScience. 2021 Dec 6;25(1):103574. doi: 10.1016/j.isci.2021.103574. eCollection 2022 Jan 21.

Authors

Jason W Miklas^{1

2}, Shiri Levy^{1

3}, Peter Hofsteen^{1

4

5}, Diego Ic Mex^{1

3}, Elisa Clark^{1

2}, Jeanot Muster^{1

2

6

7}, Aaron M Robitaille^{1

6

7}, Gargi Sivaram^{1

3}, Lauren Abell^{4

8

9}, Jamie M Goodson⁴, Inez Pranoto^{1

3}, Anup Madan¹⁰, Michael T Chin^{1

4

5

11}, Rong Tian^{1

2

3

8

9}, Charles E Murry^{1

2

4

5

11}, Randall T Moon^{1

6

7}, Yuliang Wang^{1

12}, Hannele Ruohola-Baker^{1

2

3}

Affiliations

¹ Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA 98109, USA.
² Department of Bioengineering, University of Washington, Seattle, WA 98195, USA.
³ Department of Biochemistry, University of Washington, School of Medicine, Seattle, WA 98195, USA.
⁴ Department of Pathology, University of Washington, Seattle, WA 98109, USA.
⁵ Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA.
⁶ Department of Pharmacology, University of Washington, Seattle, WA 98109, USA.
⁷ Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
⁸ Mitochondria and Metabolism Center, University of Washington, Seattle, WA 98109, USA.
⁹ Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA 98109, USA.
¹⁰ Covance Genomics Laboratory, Redmond, WA 98052, USA.
¹¹ Department of Medicine/Cardiology, University of Washington, Seattle, WA 98109, USA.
¹² Paul G. Allen School of Computer Science & Engineering, University of Washington, Seattle, WA 98195, USA.

Abstract

Heart disease is the leading cause of death with no method to repair damaged myocardium due to the limited proliferative capacity of adult cardiomyocytes. Curiously, mouse neonates and zebrafish can regenerate their hearts via cardiomyocyte de-differentiation and proliferation. However, a molecular mechanism of why these cardiomyocytes can re-enter cell cycle is poorly understood. Here, we identify a unique metabolic state that primes adult zebrafish and neonatal mouse ventricular cardiomyocytes to proliferate. Zebrafish and neonatal mouse hearts display elevated glutamine levels, predisposing them to amino-acid-driven activation of TOR, and that TOR activation is required for zebrafish cardiomyocyte regeneration in vivo. Through a multi-omics approach with cellular validation we identify metabolic and mitochondrial changes during the first week of regeneration. These data suggest that regeneration of zebrafish myocardium is driven by metabolic remodeling and reveals a unique metabolic regulator, TOR-primed state, in which zebrafish and mammalian cardiomyocytes are regeneration competent.

Keywords: Biological sciences; Cell biology; Tissue Engineering.