In vitro ketone-supported mitochondrial respiration is minimal when other substrates are readily available in cardiac and skeletal muscle
Journal article
Petrick, Heather L., Brunetta, Henver S., Pignanelli, Chris, Nunes, Everson A., van Loon, Luc J. C., Burr, Jamie F. and Holloway, Graham P.. (2020). In vitro ketone-supported mitochondrial respiration is minimal when other substrates are readily available in cardiac and skeletal muscle. The Journal of Physiology. 598(21), pp. 4869-4885. https://doi.org/10.1113/JP280032
Authors | Petrick, Heather L., Brunetta, Henver S., Pignanelli, Chris, Nunes, Everson A., van Loon, Luc J. C., Burr, Jamie F. and Holloway, Graham P. |
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Abstract | Ketone bodies (KB) have recently gained popularity as an alternative fuel source to support mitochondrial oxidative phosphorylation and enhance exercise performance. However, given the low activity of ketolytic enzymes and potential inhibition from carbohydrate oxidation, it remains unknown if KBs can contribute to energy production. We therefore determined the ability of KBs (sodium dl-β-hydroxybutyrate, β-HB; lithium acetoacetate, AcAc) to stimulate in vitro mitochondrial respiration in the left ventricle (LV) and red gastrocnemius (RG) of rats, and in human vastus lateralis. Compared to pyruvate, the ability of KBs to maximally drive respiration was low in isolated mitochondria and permeabilized fibres (PmFb) from the LV (∼30–35% of pyruvate), RG (∼10–30%), and human vastus lateralis (∼2–10%). In PmFb, the concentration of KBs required to half-maximally drive respiration (LV: 889 µm β-HB, 801 µm AcAc; RG: 782 µm β-HB, 267 µm AcAc) were greater than KB content representative of the muscle microenvironment (∼100 µm). This would predict low rates (∼1–4% of pyruvate) of biological KB-supported respiration in the LV (8–14 pmol s−1 mg−1) and RG (3–6 pmol s−1 mg−1) at rest and following exercise. Moreover, KBs did not increase respiration in the presence of saturating pyruvate, submaximal pyruvate (100 µm) reduced the ability of physiological β-HB to drive respiration, and addition of other intracellular substrates (succinate + palmitoylcarnitine) decreased maximal KB-supported respiration. As a result, product inhibition is likely to limit KB oxidation. Altogether, the ability of KBs to drive mitochondrial respiration is minimal and they are likely to be outcompeted by other substrates, compromising their use as an important energy source. |
Keywords | bioenergetics; ketone bodies; metabolism; mitochondria |
Year | 2020 |
Journal | The Journal of Physiology |
Journal citation | 598 (21), pp. 4869-4885 |
Publisher | Wiley-Blackwell Publishing Ltd. |
ISSN | 0022-3751 |
Digital Object Identifier (DOI) | https://doi.org/10.1113/JP280032 |
Scopus EID | 2-s2.0-85089518853 |
Open access | Published as green open access |
Page range | 4869-4885 |
Funder | Natural Sciences and Engineering Research Council of Canada (NSERC) |
Coordination for the Improvement in Higher Education Personnel (CAPES) | |
Author's accepted manuscript | License All rights reserved File Access Level Open |
Publisher's version | License All rights reserved File Access Level Controlled |
Output status | Published |
Publication dates | |
Online | 19 Aug 2020 |
Publication process dates | |
Accepted | 31 Jul 2020 |
Deposited | 28 May 2021 |
Grant ID | 400362 |
https://acuresearchbank.acu.edu.au/item/8w1y7/in-vitro-ketone-supported-mitochondrial-respiration-is-minimal-when-other-substrates-are-readily-available-in-cardiac-and-skeletal-muscle
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AM_Petrick_2020_In_vitro_ketone-supported_mitochondrial_respiration.pdf | |
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File access level: Open |
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