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

Brendan M Gabriel; Mustafa Al-Tarrah; Yosra 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

PLoS One. 2017 Nov 2;12(11):e0185789. doi: 10.1371/journal.pone.0185789. eCollection 2017.

Authors

Brendan M Gabriel^{1

2}, Mustafa Al-Tarrah¹, Yosra Alhindi¹, Audrius Kilikevicius³, Tomas Venckunas³, Stuart R Gray⁴, Arimantas Lionikas¹, Aivaras Ratkevicius³

Affiliations

¹ School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, Scotland, United Kingdom.
² Integrative Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
³ Department of Applied Biology and Rehabilitation, Lithuanian Sports University, Kaunas, Lithuania.
⁴ Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom.

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.

MeSH terms

Animals
Citrate (si)-Synthase / metabolism*
Lipid Metabolism*
Mice
Muscles / metabolism*
Polymorphism, Genetic*

Substances

Citrate (si)-Synthase

Grants and 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.).