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Impaired skeletal muscle mitochondrial pyruvate uptake rewires glucose metabolism to drive whole-body leanness

Research Article
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Cite this article as: eLife 2019;8:e45873 doi: 10.7554/eLife.45873

Abstract

Metabolic cycles are a fundamental element of cellular and organismal function. Among the most critical in higher organisms is the Cori Cycle, the systemic cycling between lactate and glucose. Here, skeletal muscle-specific Mitochondrial Pyruvate Carrier (MPC) deletion in mice diverted pyruvate into circulating lactate. This switch disinhibited muscle fatty acid oxidation and drove Cori Cycling that contributed to increased energy expenditure. Loss of muscle MPC activity led to strikingly decreased adiposity with complete muscle mass and strength retention. Notably, despite decreasing muscle glucose oxidation, muscle MPC disruption increased muscle glucose uptake and whole-body insulin sensitivity. Furthermore, chronic and acute muscle MPC deletion accelerated fat mass loss on a normal diet after high fat diet-induced obesity. Our results illuminate the role of the skeletal muscle MPC as a whole-body carbon flux control point. They highlight the potential utility of decreasing muscle pyruvate utilization to ameliorate obesity and type 2 diabetes.

Article and author information

Author details

  1. Arpit Sharma

    Department of Biochemistry, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Lalita Oonthonpan

    Department of Biochemistry, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Ryan D Sheldon

    Department of Biochemistry, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Adam J Rauckhorst

    Department of Biochemistry, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Zhiyong Zhu

    Department of Internal Medicine, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Sean C Tompkins

    Department of Biochemistry, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Kevin Cho

    Department of Chemistry, Washington University in St Louis, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Wojciech J Grzesik

    Fraternal Order of the Eagles Diabetes Research Center (FOEDRC), University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Lawrence R Gray

    Department of Biochemistry, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Diego A Scerbo

    Department of Biochemistry, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Alvin D Pewa

    Department of Biochemistry, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Emily M Cushing

    Department of Biochemistry, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9495-802X
  13. Michael C Dyle

    Department of Internal Medicine, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. James E Cox

    Department of Biochemistry, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Chris Adams

    Department of Internal Medicine, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Brandon S Davies

    Department of Biochemistry, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Richard K Shields

    Department of Physical Therapy and Rehabilitation Science, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. Andrew W Norris

    Department of Biochemistry, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  19. Gary Patti

    FOEDRC Metabolomics Core Facility, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3748-6193
  20. Leonid V Zingman

    Department of Internal Medicine, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  21. Eric B Taylor

    Department of Biochemistry, University of Iowa, Iowa City, United States
    For correspondence
    eric-taylor@uiowa.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4549-6567

Funding

National Institutes of Health (DK104998)

  • Eric B Taylor

National Institutes of Health (GM007337)

  • Sean C Tompkins

National Institutes of Health (HL007638)

  • Adam J Rauckhorst

National Institutes of Health (DK101183)

  • Lawrence R Gray

American Diabetes Association (1-18-PDF-060)

  • Adam J Rauckhorst

National Institutes of Health (DK112751)

  • Diego A Scerbo

National Institutes of Health (AR059190)

  • Eric B Taylor

National Institutes of Health (HD084645)

  • Richard K Shields

National Institutes of Health (HD082109)

  • Richard K Shields

National Institutes of Health (DK092412)

  • Leonid V Zingman

National Institutes of Health (ES028365)

  • Gary Patti

National Institutes of Health (HL130146)

  • Brandon S Davies

National Institutes of Health (HL007344)

  • Ryan D Sheldon

National Institutes of Health (DK116522)

  • Ryan D Sheldon

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animal work was performed in accordance with the University of Iowa Animal Use and Care Committee (IACUC). The University of Iowa IACUC is accredited by AALACi (#000833), is a Registered United States Department of Agriculture research facility (USDA No. 42-R-0004), and has PHS Approved Animal Welfare Assurance (#D16-00009).

Reviewing Editor

  1. David E James, The University of Sydney, Australia

Publication history

  1. Received: February 7, 2019
  2. Accepted: July 15, 2019
  3. Accepted Manuscript published: July 15, 2019 (version 1)
  4. Accepted Manuscript updated: July 18, 2019 (version 2)
  5. Version of Record published: August 6, 2019 (version 3)

Copyright

© 2019, Sharma et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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