iScience (Jan 2022)
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
Affiliations
- Jason W. Miklas
- Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA 98109, USA; Department of Bioengineering, University of Washington, Seattle, WA 98195, USA
- Shiri Levy
- Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA 98109, USA; Department of Biochemistry, University of Washington, School of Medicine, Seattle, WA 98195, USA
- Peter Hofsteen
- Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA 98109, USA; Department of Pathology, University of Washington, Seattle, WA 98109, USA; Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA
- Diego Ic Mex
- Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA 98109, USA; Department of Biochemistry, University of Washington, School of Medicine, Seattle, WA 98195, USA
- Elisa Clark
- Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA 98109, USA; Department of Bioengineering, University of Washington, Seattle, WA 98195, USA
- Jeanot Muster
- Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA 98109, USA; Department of Bioengineering, University of Washington, Seattle, WA 98195, USA; Department of Pharmacology, University of Washington, Seattle, WA 98109, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
- Aaron M. Robitaille
- Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA 98109, USA; Department of Pharmacology, University of Washington, Seattle, WA 98109, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
- Gargi Sivaram
- Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA 98109, USA; Department of Biochemistry, University of Washington, School of Medicine, Seattle, WA 98195, USA
- Lauren Abell
- Department of Pathology, University of Washington, Seattle, WA 98109, USA; Mitochondria and Metabolism Center, University of Washington, Seattle, WA 98109, USA; Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA 98109, USA
- Jamie M. Goodson
- Department of Pathology, University of Washington, Seattle, WA 98109, USA
- Inez Pranoto
- Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA 98109, USA; Department of Biochemistry, University of Washington, School of Medicine, Seattle, WA 98195, USA
- Anup Madan
- Covance Genomics Laboratory, Redmond, WA 98052, USA
- Michael T. Chin
- Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA 98109, USA; Department of Pathology, University of Washington, Seattle, WA 98109, USA; Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA; Department of Medicine/Cardiology, University of Washington, Seattle, WA 98109, USA
- Rong Tian
- Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA 98109, USA; Department of Bioengineering, University of Washington, Seattle, WA 98195, USA; Department of Biochemistry, University of Washington, School of Medicine, Seattle, WA 98195, USA; Mitochondria and Metabolism Center, University of Washington, Seattle, WA 98109, USA; Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA 98109, USA
- Charles E. Murry
- Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA 98109, USA; Department of Bioengineering, University of Washington, Seattle, WA 98195, USA; Department of Pathology, University of Washington, Seattle, WA 98109, USA; Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA; Department of Medicine/Cardiology, University of Washington, Seattle, WA 98109, USA
- Randall T. Moon
- Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA 98109, USA; Department of Pharmacology, University of Washington, Seattle, WA 98109, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
- Yuliang Wang
- Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA 98109, USA; Paul G. Allen School of Computer Science & Engineering, University of Washington, Seattle, WA 98195, USA
- Hannele Ruohola-Baker
- Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA 98109, USA; Department of Bioengineering, University of Washington, Seattle, WA 98195, USA; Department of Biochemistry, University of Washington, School of Medicine, Seattle, WA 98195, USA; Corresponding author
- Journal volume & issue
-
Vol. 25,
no. 1
p. 103574
Abstract
Summary: 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.
