H55N polymorphism as a likely cause of variation in citrate synthase activity of mouse skeletal muscle

Ratkevičius, Aivaras; Carroll, Andrew M.; Kilikevičius, Audrius; Venckūnas, Tomas; McDermott, Kevin T.; Gray, Stuart R.; Wackerhage, Henning; Lionikas, Arimantas

doi:10.1152/physiolgenomics.00066.2010

Cited by 22 publications

(32 citation statements)

References 37 publications

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“…The CS encoding gene, Cs , resides in the telomeric region of mouse Chr 10. The A/J strain is characterized by ~50% reduced enzymatic activity of CS in skeletal muscle (Ratkevicius et al, 2010). Consistently with that, albeit a smaller reduction of ~35% was observed in the present study in B6.A10 strain carrying the A/J strain Chromosome 10.…”

Section: Discussionmentioning

confidence: 99%

“…CS activity was measured as previously described (Ratkevicius et al, 2010). The gastrocnemius muscle samples from the B6 ( n = 9) and B6.A10 ( n = 9) males were homogenized in ice-cold lysis buffer (50 mM Tris·HCl, 1 mM EDTA, 1 mM EGTA, 1% Triton X-100, pH was adjusted to 7.0) with an ULTRA-TURRAX homogenizer (Rose Scientific, Edmonton, Canada).…”

Section: Methodsmentioning

confidence: 99%

“…Furthermore, A/J mice carry a strain-specific allele of the gene. We have reported that enzymatic activity of CS in skeletal muscle samples from the A/J strain is ~50% lower compared to B6 allele (Ratkevicius et al, 2010). As an initial step to investigating the role of the genes residing on Chr 10 in endurance capacity of the A/J mice, we used the B6.A10 consomic strain to explore relevant phenotypes.…”

Section: Introductionmentioning

confidence: 93%

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Forced Running Endurance Is Influenced by Gene(s) on Mouse Chromosome 10

et al. 2017

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Phenotypic diversity between laboratory mouse strains provides a model for studying the underlying genetic mechanisms. The A/J strain performs poorly in various endurance exercise models. The aim of the study was to test if endurance capacity and contractility of the fast- and slow-twitch muscles are affected by the genes on mouse chromosome 10. The C57BL/6J (B6) strain and C57BL/6J-Chr 10A/J/NaJ (B6.A10) consomic strain which carries the A/J chromosome 10 on a B6 strain background were compared. The B6.A10 mice compared to B6 were larger in body weight (p < 0.02): 27.2 ± 1.9 vs. 23.8 ± 2.7 and 23.4 ± 1.9 vs. 22.9 ± 2.3 g, for males and females, respectively, and in male soleus weight (p < 0.02): 9.7 ± 0.4 vs. 8.6 ± 0.9 mg. In the forced running test the B6.A10 mice completed only 64% of the B6 covered distance (p < 0.0001). However, there was no difference in voluntary wheel running (p = 0.6) or in fatigability of isolated soleus (p = 0.24) or extensor digitorum longus (EDL, p = 0.7) muscles. We conclude that chromosome 10 of the A/J strain contributes to reduced endurance performance. We also discuss physiological mechanisms and methodological aspects relevant to interpretation of these findings.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 93%

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Forced Running Endurance Is Influenced by Gene(s) on Mouse Chromosome 10

et al. 2017

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“…The PolyPhen computer tool (http://coot.embl.de/PolyPhen/), which uses both phylogenetic and structural information to assess the impact of amino acid substitutions on protein function, predicts that the H55N mutation is probably damaging. But the strongest evidence for the deleterious nature of the H55N mutation on protein function comes from a recent investigation into the cause of low CS activity (50-65% reduction) in skeletal muscle of A/J mice compared with other strains (Ratkevicius et al, 2010). This study showed that A/J mice have the same CS and mitochondrial protein content as mice of other strains, but differ in CS enzyme kinetics and catalytic properties, thereby implicating the H55N mutation as the most likely cause for the low CS activity of this strain.…”

Section: Discussionmentioning

confidence: 99%

Association of a citrate synthase missense mutation with age-related hearing loss in A/J mice

Johnson

Gagnon

Longo-Guess

et al. 2012

Neurobiology of Aging

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We previously mapped a locus (ahl4) on distal Chromosome 10 that contributes to the age-related hearing loss of A/J strain mice. Here, we report on a refined genetic map position for ahl4 and its association with a mutation in the citrate synthase gene (Cs). We mapped ahl4 to the distal-most 7 Mb of Chromosome 10 by analysis of a new linkage backcross and then further narrowed the interval to 5.5 Mb by analysis of eight C57BL/6J congenic lines with different A/J-derived segments of Chr 10. A nucleotide variant in exon 3 of Cs is the only known DNA difference within the ahl4 candidate gene interval that is unique to the A/J strain and that causes a nonsynonymous codon change. Multiple lines of evidence implicate this missense mutation (H55N) as the underlying cause of ahl4-related hearing loss, likely through its effects on mitochondrial ATP and free radical production in cochlear hair cells. The A/J mouse thus provides a new model system for in vivo studies of mitochondrial function and hearing loss.

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“…The RT PCR procedure has been described in detail [61]. The images of the PCR products were quantified using ImageJ software (NIH – version 1.43).…”

Section: Methodsmentioning

confidence: 99%

Resolving candidate genes of mouse skeletal muscle QTL via RNA-Seq and expression network analyses

et al. 2012

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BackgroundWe have recently identified a number of Quantitative Trait Loci (QTL) contributing to the 2-fold muscle weight difference between the LG/J and SM/J mouse strains and refined their confidence intervals. To facilitate nomination of the candidate genes responsible for these differences we examined the transcriptome of the tibialis anterior (TA) muscle of each strain by RNA-Seq.Results13,726 genes were expressed in mouse skeletal muscle. Intersection of a set of 1061 differentially expressed transcripts with a mouse muscle Bayesian Network identified a coherent set of differentially expressed genes that we term the LG/J and SM/J Regulatory Network (LSRN). The integration of the QTL, transcriptome and the network analyses identified eight key drivers of the LSRN (Kdr, Plbd1, Mgp, Fah, Prss23, 2310014F06Rik, Grtp1, Stk10) residing within five QTL regions, which were either polymorphic or differentially expressed between the two strains and are strong candidates for quantitative trait genes (QTGs) underlying muscle mass. The insight gained from network analysis including the ability to make testable predictions is illustrated by annotating the LSRN with knowledge-based signatures and showing that the SM/J state of the network corresponds to a more oxidative state. We validated this prediction by NADH tetrazolium reductase staining in the TA muscle revealing higher oxidative potential of the SM/J compared to the LG/J strain (p<0.03).ConclusionThus, integration of fine resolution QTL mapping, RNA-Seq transcriptome information and mouse muscle Bayesian Network analysis provides a novel and unbiased strategy for nomination of muscle QTGs.

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H55N polymorphism as a likely cause of variation in citrate synthase activity of mouse skeletal muscle

Cited by 22 publications

References 37 publications

Forced Running Endurance Is Influenced by Gene(s) on Mouse Chromosome 10

Forced Running Endurance Is Influenced by Gene(s) on Mouse Chromosome 10

Association of a citrate synthase missense mutation with age-related hearing loss in A/J mice

Resolving candidate genes of mouse skeletal muscle QTL via RNA-Seq and expression network analyses

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