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.
Highlights
Mitochondria play a key role in metabolic health and functioning of skeletal muscle [1,2]
We used lentivirus delivered stable gene silencing to knock down Cs expression in C2C12 muscle cells and Cs mRNA to β-Actin mRNA ratio was consistently lower in Cs shRNA cells compared to Con shRNA cells (0.022 ± 007 versus 0.081 ± 016, respectively, p < 0.001)
We tested the hypothesis that the A/J variant of the H55N polymorphism is associated with low Citrate synthase (CS) activity
Summary
Mitochondria play a key role in metabolic health and functioning of skeletal muscle [1,2]. The maximal capacity of CS to produce citrate exceeds the rate of use in the Krebs cycle by more than 10 times, even when assessed in skeletal muscles during exercise at a maximal aerobic capacity [6] In agreement with these calculations, cytosolic citrate levels increase significantly in skeletal muscles of rats after glucose infusion which increases substrate availability for citrate synthesis in mitochondria [7]. These findings suggest that CS activity might be higher than needed to sustain mitochondrial function
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