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Altered Ca2+ kinetics associated with α-actinin-3 deficiency may explain positive selection for ACTN3 allele in human evolution.

Head SI, Chan S, Houweling PJ, Quinlan KG, Murphy R, Wagner S, Friedrich O, North KN - PLoS Genet. (2015)

Bottom Line: Over 1.5 billion people lack the skeletal muscle fast-twitch fibre protein α-actinin-3 due to homozygosity for a common polymorphism (R577X) in the ACTN3 gene. α-Actinin-3 deficiency is detrimental to sprint performance in elite athletes and beneficial to endurance activities.Prolonged exposure to cold can also induce changes in skeletal muscle similar to those observed with endurance training, and changes in Ca2+ handling by the sarcoplasmic reticulum (SR) are a key factor underlying these adaptations.On this basis, we explored the effects of α-actinin-3 deficiency on Ca2+ kinetics in single flexor digitorum brevis muscle fibres from Actn3 KO mice, using the Ca2+-sensitive dye fura-2.

View Article: PubMed Central - PubMed

Affiliation: School of Medical Sciences, University of New South Wales, Sydney, Australia.

ABSTRACT
Over 1.5 billion people lack the skeletal muscle fast-twitch fibre protein α-actinin-3 due to homozygosity for a common polymorphism (R577X) in the ACTN3 gene. α-Actinin-3 deficiency is detrimental to sprint performance in elite athletes and beneficial to endurance activities. In the human genome, it is very difficult to find single-gene loss-of-function variants that bear signatures of positive selection, yet intriguingly, the ACTN3 variant has undergone strong positive selection during recent evolution, appearing to provide a survival advantage where food resources are scarce and climate is cold. We have previously demonstrated that α-actinin-3 deficiency in the Actn3 KO mouse results in a shift in fast-twitch fibres towards oxidative metabolism, which would be more "energy efficient" in famine, and beneficial to endurance performance. Prolonged exposure to cold can also induce changes in skeletal muscle similar to those observed with endurance training, and changes in Ca2+ handling by the sarcoplasmic reticulum (SR) are a key factor underlying these adaptations. On this basis, we explored the effects of α-actinin-3 deficiency on Ca2+ kinetics in single flexor digitorum brevis muscle fibres from Actn3 KO mice, using the Ca2+-sensitive dye fura-2. Compared to wild-type, fibres of Actn3 KO mice showed: (i) an increased rate of decay of the twitch transient; (ii) a fourfold increase in the rate of SR Ca2+ leak; (iii) a threefold increase in the rate of SR Ca2+ pumping; and (iv) enhanced maintenance of tetanic Ca2+ during fatigue. The SR Ca2+ pump, SERCA1, and the Ca2+-binding proteins, calsequestrin and sarcalumenin, showed markedly increased expression in muscles of KO mice. Together, these changes in Ca2+ handling in the absence of α-actinin-3 are consistent with cold acclimatisation and thermogenesis, and offer an additional explanation for the positive selection of the ACTN3 577X allele in populations living in cold environments during recent evolution.

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SR pump function in FDB fibres of WT and Actn3 KO mice.A Relationship between [Ca2+]i and −d[Ca2+]i /dt (rate of [Ca2+]i decline) at selected time points during the slow phase of decay in twitch transients. Each point represents the mean ± S.E.M. across all twitch transients analysed in WT and KO fibres. The continuous lines are the SR pump function curves fitted to the points using the equation shown. B The parameter A, which reflects the rate of Ca2+ uptake by the SR pump, was significantly higher in fibres of KO mice. C The parameter L, which represents the rate of Ca2+ leak from the SR, was significantly higher in fibres of KO mice. (In all figures, n = 9 for WT and n = 9 for KO.)
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pgen.1004862.g002: SR pump function in FDB fibres of WT and Actn3 KO mice.A Relationship between [Ca2+]i and −d[Ca2+]i /dt (rate of [Ca2+]i decline) at selected time points during the slow phase of decay in twitch transients. Each point represents the mean ± S.E.M. across all twitch transients analysed in WT and KO fibres. The continuous lines are the SR pump function curves fitted to the points using the equation shown. B The parameter A, which reflects the rate of Ca2+ uptake by the SR pump, was significantly higher in fibres of KO mice. C The parameter L, which represents the rate of Ca2+ leak from the SR, was significantly higher in fibres of KO mice. (In all figures, n = 9 for WT and n = 9 for KO.)

Mentions: Fig. 2A shows the SR pump function curves for FDB fibres from WT and Actn3 KO mice. Each curve shows the relationship between [Ca2+]i and the rate of [Ca2+]i decline during the slow phase of [Ca2+]i decay. It is clear that for any level of [Ca2+]i, the rate of [Ca2+]i decline is higher in KO than in WT. The rate of [Ca2+]i decline is a balance between the rate of SR Ca2+ pumping and the rate of Ca2+ leak from the SR [21]. To distinguish between these two factors, we used the SR pump equation (Eqn 3) shown in the Methods. The value of A, which reflects the rate of pumping, was significantly higher in fibres of Actn3 KO mice (Fig. 2B). The value of L, which reflects the rate of leak, was also significantly higher in fibres of Actn3 KO mice (Fig. 2C). Hence in Actn3 KO fibres, the faster rate of Ca2+ pumping by the SR is counteracted by a faster rate of Ca2+ leak from the SR, but overall, [Ca2+]i still declines more quickly during a twitch than in WT fibres.


Altered Ca2+ kinetics associated with α-actinin-3 deficiency may explain positive selection for ACTN3 allele in human evolution.

Head SI, Chan S, Houweling PJ, Quinlan KG, Murphy R, Wagner S, Friedrich O, North KN - PLoS Genet. (2015)

SR pump function in FDB fibres of WT and Actn3 KO mice.A Relationship between [Ca2+]i and −d[Ca2+]i /dt (rate of [Ca2+]i decline) at selected time points during the slow phase of decay in twitch transients. Each point represents the mean ± S.E.M. across all twitch transients analysed in WT and KO fibres. The continuous lines are the SR pump function curves fitted to the points using the equation shown. B The parameter A, which reflects the rate of Ca2+ uptake by the SR pump, was significantly higher in fibres of KO mice. C The parameter L, which represents the rate of Ca2+ leak from the SR, was significantly higher in fibres of KO mice. (In all figures, n = 9 for WT and n = 9 for KO.)
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4295894&req=5

pgen.1004862.g002: SR pump function in FDB fibres of WT and Actn3 KO mice.A Relationship between [Ca2+]i and −d[Ca2+]i /dt (rate of [Ca2+]i decline) at selected time points during the slow phase of decay in twitch transients. Each point represents the mean ± S.E.M. across all twitch transients analysed in WT and KO fibres. The continuous lines are the SR pump function curves fitted to the points using the equation shown. B The parameter A, which reflects the rate of Ca2+ uptake by the SR pump, was significantly higher in fibres of KO mice. C The parameter L, which represents the rate of Ca2+ leak from the SR, was significantly higher in fibres of KO mice. (In all figures, n = 9 for WT and n = 9 for KO.)
Mentions: Fig. 2A shows the SR pump function curves for FDB fibres from WT and Actn3 KO mice. Each curve shows the relationship between [Ca2+]i and the rate of [Ca2+]i decline during the slow phase of [Ca2+]i decay. It is clear that for any level of [Ca2+]i, the rate of [Ca2+]i decline is higher in KO than in WT. The rate of [Ca2+]i decline is a balance between the rate of SR Ca2+ pumping and the rate of Ca2+ leak from the SR [21]. To distinguish between these two factors, we used the SR pump equation (Eqn 3) shown in the Methods. The value of A, which reflects the rate of pumping, was significantly higher in fibres of Actn3 KO mice (Fig. 2B). The value of L, which reflects the rate of leak, was also significantly higher in fibres of Actn3 KO mice (Fig. 2C). Hence in Actn3 KO fibres, the faster rate of Ca2+ pumping by the SR is counteracted by a faster rate of Ca2+ leak from the SR, but overall, [Ca2+]i still declines more quickly during a twitch than in WT fibres.

Bottom Line: Over 1.5 billion people lack the skeletal muscle fast-twitch fibre protein α-actinin-3 due to homozygosity for a common polymorphism (R577X) in the ACTN3 gene. α-Actinin-3 deficiency is detrimental to sprint performance in elite athletes and beneficial to endurance activities.Prolonged exposure to cold can also induce changes in skeletal muscle similar to those observed with endurance training, and changes in Ca2+ handling by the sarcoplasmic reticulum (SR) are a key factor underlying these adaptations.On this basis, we explored the effects of α-actinin-3 deficiency on Ca2+ kinetics in single flexor digitorum brevis muscle fibres from Actn3 KO mice, using the Ca2+-sensitive dye fura-2.

View Article: PubMed Central - PubMed

Affiliation: School of Medical Sciences, University of New South Wales, Sydney, Australia.

ABSTRACT
Over 1.5 billion people lack the skeletal muscle fast-twitch fibre protein α-actinin-3 due to homozygosity for a common polymorphism (R577X) in the ACTN3 gene. α-Actinin-3 deficiency is detrimental to sprint performance in elite athletes and beneficial to endurance activities. In the human genome, it is very difficult to find single-gene loss-of-function variants that bear signatures of positive selection, yet intriguingly, the ACTN3 variant has undergone strong positive selection during recent evolution, appearing to provide a survival advantage where food resources are scarce and climate is cold. We have previously demonstrated that α-actinin-3 deficiency in the Actn3 KO mouse results in a shift in fast-twitch fibres towards oxidative metabolism, which would be more "energy efficient" in famine, and beneficial to endurance performance. Prolonged exposure to cold can also induce changes in skeletal muscle similar to those observed with endurance training, and changes in Ca2+ handling by the sarcoplasmic reticulum (SR) are a key factor underlying these adaptations. On this basis, we explored the effects of α-actinin-3 deficiency on Ca2+ kinetics in single flexor digitorum brevis muscle fibres from Actn3 KO mice, using the Ca2+-sensitive dye fura-2. Compared to wild-type, fibres of Actn3 KO mice showed: (i) an increased rate of decay of the twitch transient; (ii) a fourfold increase in the rate of SR Ca2+ leak; (iii) a threefold increase in the rate of SR Ca2+ pumping; and (iv) enhanced maintenance of tetanic Ca2+ during fatigue. The SR Ca2+ pump, SERCA1, and the Ca2+-binding proteins, calsequestrin and sarcalumenin, showed markedly increased expression in muscles of KO mice. Together, these changes in Ca2+ handling in the absence of α-actinin-3 are consistent with cold acclimatisation and thermogenesis, and offer an additional explanation for the positive selection of the ACTN3 577X allele in populations living in cold environments during recent evolution.

Show MeSH
Related in: MedlinePlus