H55N polymorphism is associated with low citrate synthase activity which regulates lipid metabolism in mouse muscle cells

Brendan M Gabriel; Mustafa Al-Tarrah; Yosra Zakariyya Y Alhindi; Audrius Kilikevicius; Tomas Venckunas; Stuart R Gray; Arimantas Lionikas; Aivaras Ratkevicius

doi:10.1371/journal.pone.0185789

H55N polymorphism is associated with low citrate synthase activity which regulates lipid metabolism in mouse muscle cells

Brendan M Gabriel, Mustafa Al-Tarrah, Yosra Zakariyya Y Alhindi, Audrius Kilikevicius, Tomas Venckunas, Stuart R Gray, Arimantas Lionikas, Aivaras Ratkevicius

Research output: Contribution to journal › Article › peer-review

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Abstract

The H55N polymorphism in the Cs gene of A/J mice has been linked to low activity of the enzyme in skeletal muscles. The aim of the study was to test this hypothesis and examine effects of low citrate synthase (CS) activity on palmitate metabolism in muscle cells. Results of the study showed that carriers of the wild type (WT) Cs (C57BL/6J and Balb/cByJ mouse strains) had higher CS activity (p < 0.01) than carriers of the A/J variant (B6.A-(rs3676616-D10Utsw1)/KjnB6 and A/J mouse strains) in the heart, liver and gastrocnemius muscle. Furthermore, the recombinant CS protein of WT showed higher CS activity than the A/J variant. In C2C12 muscle cells the shRNA mediated 47% knockdown of CS activity reduced the rate of fatty acid oxidation compared to the control cells. In summary, our results are consistent with the hypothesis that H55N substitution causes a reduction in CS activity. Furthermore, low CS activity interferes with metabolic flexibility of muscle cells.

Original language	English
Article number	e0185789
Pages (from-to)	1-20
Number of pages	20
Journal	PloS ONE
Volume	12
Issue number	11
DOIs	https://doi.org/10.1371/journal.pone.0185789
Publication status	Published - 2 Nov 2017

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H55N polymorphism is associated with low citrate synthase activity which regulates lipid metabolism in mouse muscle cells
Copyright: © 2017 Gabriel et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. https://creativecommons.org/licenses/by/4.0/
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http://europepmc.org/articles/PMC5667803

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Brendan Gabriel
- School of Medicine, Medical Sciences & Nutrition, The Rowett Institute of Nutrition and Health - Research Fellow
Person: Academic Related - Research
Arimantas Lionikas
- Clinical Medicine
- School of Medicine, Medical Sciences & Nutrition, Medical Sciences - Senior Lecturer
- Institute of Medical Sciences
Person: Academic

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H55N polymorphism is associated with low citrate synthase activity which regulates lipid metabolism in mouse muscle cells. / Gabriel, Brendan M; Al-Tarrah, Mustafa; Alhindi, Yosra Zakariyya Y; Kilikevicius, Audrius; Venckunas, Tomas; Gray, Stuart R; Lionikas, Arimantas; Ratkevicius, Aivaras.

In: PloS ONE, Vol. 12, No. 11, e0185789, 02.11.2017, p. 1-20.

Research output: Contribution to journal › Article › peer-review

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title = "H55N polymorphism is associated with low citrate synthase activity which regulates lipid metabolism in mouse muscle cells",

abstract = "The H55N polymorphism in the Cs gene of A/J mice has been linked to low activity of the enzyme in skeletal muscles. The aim of the study was to test this hypothesis and examine effects of low citrate synthase (CS) activity on palmitate metabolism in muscle cells. Results of the study showed that carriers of the wild type (WT) Cs (C57BL/6J and Balb/cByJ mouse strains) had higher CS activity (p < 0.01) than carriers of the A/J variant (B6.A-(rs3676616-D10Utsw1)/KjnB6 and A/J mouse strains) in the heart, liver and gastrocnemius muscle. Furthermore, the recombinant CS protein of WT showed higher CS activity than the A/J variant. In C2C12 muscle cells the shRNA mediated 47% knockdown of CS activity reduced the rate of fatty acid oxidation compared to the control cells. In summary, our results are consistent with the hypothesis that H55N substitution causes a reduction in CS activity. Furthermore, low CS activity interferes with metabolic flexibility of muscle cells.",

author = "Gabriel, {Brendan M} and Mustafa Al-Tarrah and Alhindi, {Yosra Zakariyya Y} and Audrius Kilikevicius and Tomas Venckunas and Gray, {Stuart R} and Arimantas Lionikas and Aivaras Ratkevicius",

note = "Funding: This work was supported, in whole or in part, by European Social Fund under the Global Grant measure Grant VP1-3.1-{\v S}MM-07-K-02-057 (to A.L.), European Foundation for the Study of Diabetes grant (to T.V.), NHS Grampian Endowment grant (to A.R. and S.R.G.), Kuwait Ministry of Health grant (to M.A.), Saudi Ministry of Higher Education grant (to Y.A.,) as well as Saltire scholarship, Wenner-Gren Foundation Postdoctoral Fellowship, Albert Renold Travel Fellowship and a Novo Nordisk Foundation Challenge Grant (to B.G.).",

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AU - Kilikevicius, Audrius

AU - Venckunas, Tomas

AU - Gray, Stuart R

AU - Lionikas, Arimantas

AU - Ratkevicius, Aivaras

N1 - Funding: This work was supported, in whole or in part, by European Social Fund under the Global Grant measure Grant VP1-3.1-ŠMM-07-K-02-057 (to A.L.), European Foundation for the Study of Diabetes grant (to T.V.), NHS Grampian Endowment grant (to A.R. and S.R.G.), Kuwait Ministry of Health grant (to M.A.), Saudi Ministry of Higher Education grant (to Y.A.,) as well as Saltire scholarship, Wenner-Gren Foundation Postdoctoral Fellowship, Albert Renold Travel Fellowship and a Novo Nordisk Foundation Challenge Grant (to B.G.).

PY - 2017/11/2

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N2 - The H55N polymorphism in the Cs gene of A/J mice has been linked to low activity of the enzyme in skeletal muscles. The aim of the study was to test this hypothesis and examine effects of low citrate synthase (CS) activity on palmitate metabolism in muscle cells. Results of the study showed that carriers of the wild type (WT) Cs (C57BL/6J and Balb/cByJ mouse strains) had higher CS activity (p < 0.01) than carriers of the A/J variant (B6.A-(rs3676616-D10Utsw1)/KjnB6 and A/J mouse strains) in the heart, liver and gastrocnemius muscle. Furthermore, the recombinant CS protein of WT showed higher CS activity than the A/J variant. In C2C12 muscle cells the shRNA mediated 47% knockdown of CS activity reduced the rate of fatty acid oxidation compared to the control cells. In summary, our results are consistent with the hypothesis that H55N substitution causes a reduction in CS activity. Furthermore, low CS activity interferes with metabolic flexibility of muscle cells.

AB - The H55N polymorphism in the Cs gene of A/J mice has been linked to low activity of the enzyme in skeletal muscles. The aim of the study was to test this hypothesis and examine effects of low citrate synthase (CS) activity on palmitate metabolism in muscle cells. Results of the study showed that carriers of the wild type (WT) Cs (C57BL/6J and Balb/cByJ mouse strains) had higher CS activity (p < 0.01) than carriers of the A/J variant (B6.A-(rs3676616-D10Utsw1)/KjnB6 and A/J mouse strains) in the heart, liver and gastrocnemius muscle. Furthermore, the recombinant CS protein of WT showed higher CS activity than the A/J variant. In C2C12 muscle cells the shRNA mediated 47% knockdown of CS activity reduced the rate of fatty acid oxidation compared to the control cells. In summary, our results are consistent with the hypothesis that H55N substitution causes a reduction in CS activity. Furthermore, low CS activity interferes with metabolic flexibility of muscle cells.

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H55N polymorphism is associated with low citrate synthase activity which regulates lipid metabolism in mouse muscle cells

Abstract

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Brendan Gabriel

Arimantas Lionikas

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