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FAT/CD36-null mice reveal that mitochondrial FAT/CD36 is required to upregulate mitochondrial fatty acid oxidation in contracting muscle.

Abstract

The plasma membrane fatty acid transport protein FAT/CD36 is also present at the mitochondria, where it may contribute to the regulation of fatty acid oxidation, although this has been challenged. Therefore, we have compared enzyme activities and rates of mitochondrial palmitate oxidation in muscles of wild-type (WT) and FAT/CD36 knockout (KO) mice, at rest and after muscle contraction. In WT and KO mice, carnitine palmitoyltransferase-I, citrate synthase, and beta-hydroxyacyl-CoA dehydrogenase activities did not differ in subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondria of WT and FAT/CD36 KO mice. Basal palmitate oxidation rates were lower (P < 0.05) in KO mice (SS -18%; IMF -13%). Muscle contraction increased fatty acid oxidation (+18%) and mitochondrial FAT/CD36 protein (+16%) in WT IMF but not in WT SS, or in either mitochondrial subpopulation in KO mice. This revealed that the difference in IMF mitochondrial fatty acid oxidation between WT and KO mice can be increased approximately 2.5-fold from 13% under basal conditions to 35% during muscle contraction. The FAT/CD36 inhibitor sulfo-N-succinimidyl oleate (SSO), inhibited palmitate transport across the plasma membrane in WT, but not in KO mice. In contrast, SSO bound to mitochondrial membranes and reduced palmitate oxidation rates to a similar extent in both WT and KO mitochondria (approximately 80%; P < 0.05). In addition, SSO reduced state III respiration with succinate as a substrate, without altering mitochondrial coupling (P/O ratios). Thus, while SSO inhibits FAT/CD36-mediated palmitate transport at the plasma membrane, SSO has undefined effects on mitochondria. Nevertheless, the KO animals reveal that FAT/CD36 contributes to the regulation of mitochondrial fatty acid oxidation, which is especially important for meeting the increased metabolic demands during muscle contraction.

Authors+Show Affiliations

1Department of Human Health & Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada. ghollowa@uoguelph.caNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19625692

Citation

Holloway, Graham P., et al. "FAT/CD36-null Mice Reveal That Mitochondrial FAT/CD36 Is Required to Upregulate Mitochondrial Fatty Acid Oxidation in Contracting Muscle." American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, vol. 297, no. 4, 2009, pp. R960-7.
Holloway GP, Jain SS, Bezaire V, et al. FAT/CD36-null mice reveal that mitochondrial FAT/CD36 is required to upregulate mitochondrial fatty acid oxidation in contracting muscle. Am J Physiol Regul Integr Comp Physiol. 2009;297(4):R960-7.
Holloway, G. P., Jain, S. S., Bezaire, V., Han, X. X., Glatz, J. F., Luiken, J. J., ... Bonen, A. (2009). FAT/CD36-null mice reveal that mitochondrial FAT/CD36 is required to upregulate mitochondrial fatty acid oxidation in contracting muscle. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, 297(4), pp. R960-7. doi:10.1152/ajpregu.91021.2008.
Holloway GP, et al. FAT/CD36-null Mice Reveal That Mitochondrial FAT/CD36 Is Required to Upregulate Mitochondrial Fatty Acid Oxidation in Contracting Muscle. Am J Physiol Regul Integr Comp Physiol. 2009;297(4):R960-7. PubMed PMID: 19625692.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - FAT/CD36-null mice reveal that mitochondrial FAT/CD36 is required to upregulate mitochondrial fatty acid oxidation in contracting muscle. AU - Holloway,Graham P, AU - Jain,Swati S, AU - Bezaire,Veronic, AU - Han,Xiao Xia, AU - Glatz,Jan F C, AU - Luiken,Joost J F P, AU - Harper,Mary-Ellen, AU - Bonen,Arend, Y1 - 2009/07/22/ PY - 2009/7/24/entrez PY - 2009/7/25/pubmed PY - 2009/10/14/medline SP - R960 EP - 7 JF - American journal of physiology. Regulatory, integrative and comparative physiology JO - Am. J. Physiol. Regul. Integr. Comp. Physiol. VL - 297 IS - 4 N2 - The plasma membrane fatty acid transport protein FAT/CD36 is also present at the mitochondria, where it may contribute to the regulation of fatty acid oxidation, although this has been challenged. Therefore, we have compared enzyme activities and rates of mitochondrial palmitate oxidation in muscles of wild-type (WT) and FAT/CD36 knockout (KO) mice, at rest and after muscle contraction. In WT and KO mice, carnitine palmitoyltransferase-I, citrate synthase, and beta-hydroxyacyl-CoA dehydrogenase activities did not differ in subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondria of WT and FAT/CD36 KO mice. Basal palmitate oxidation rates were lower (P < 0.05) in KO mice (SS -18%; IMF -13%). Muscle contraction increased fatty acid oxidation (+18%) and mitochondrial FAT/CD36 protein (+16%) in WT IMF but not in WT SS, or in either mitochondrial subpopulation in KO mice. This revealed that the difference in IMF mitochondrial fatty acid oxidation between WT and KO mice can be increased approximately 2.5-fold from 13% under basal conditions to 35% during muscle contraction. The FAT/CD36 inhibitor sulfo-N-succinimidyl oleate (SSO), inhibited palmitate transport across the plasma membrane in WT, but not in KO mice. In contrast, SSO bound to mitochondrial membranes and reduced palmitate oxidation rates to a similar extent in both WT and KO mitochondria (approximately 80%; P < 0.05). In addition, SSO reduced state III respiration with succinate as a substrate, without altering mitochondrial coupling (P/O ratios). Thus, while SSO inhibits FAT/CD36-mediated palmitate transport at the plasma membrane, SSO has undefined effects on mitochondria. Nevertheless, the KO animals reveal that FAT/CD36 contributes to the regulation of mitochondrial fatty acid oxidation, which is especially important for meeting the increased metabolic demands during muscle contraction. SN - 1522-1490 UR - https://www.unboundmedicine.com/medline/citation/19625692/FAT/CD36_null_mice_reveal_that_mitochondrial_FAT/CD36_is_required_to_upregulate_mitochondrial_fatty_acid_oxidation_in_contracting_muscle_ L2 - http://www.physiology.org/doi/full/10.1152/ajpregu.91021.2008?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -