Impaired skeletal muscle mitochondrial pyruvate uptake rewires glucose metabolism to drive whole-body leanness
- University of Iowa, United States
- Washington University in St Louis, United States
- University of Utah, United States
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.
Data availability
All metabolomic results generated as part of this study are provided in Supplemental tables 2 and 3 related to Figure 5.
Article and author information
Author details
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.
Reviewing Editor
- David E James, The University of Sydney, Australia
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).
Version history
- Received: February 7, 2019
- Accepted: July 15, 2019
- Accepted Manuscript published: July 15, 2019 (version 1)
- Accepted Manuscript updated: July 18, 2019 (version 2)
- 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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Impaired skeletal muscle mitochondrial pyruvate uptake rewires glucose metabolism to drive whole-body leanness
eLife 8:e45873.
https://doi.org/10.7554/eLife.45873
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