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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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Ca2+ kinetics of single twitches in FDB fibres from WT and Actn3 KO mice.A Superimposed representative twitch transients from an Actn3 KO and a WT fibre, showing faster [Ca2+]i decay in the KO fibre. Across our sample as a whole, there was no difference between WT and Actn3 KO fibres in the time taken to rise from 20% to 80% of peak (B). However, during decay, the rate constant of decay was significantly higher in Actn3 KO fibres than in WT fibres, both during the fast phase (C) and slow phase (D). (In B, C and D, n = 36 for WT and n = 31 for KO. In C and D, equivalent time constants, in ms, are: 2.2 ± 0.1 for WT and 1.6 ± 0.1 for KO in fast phase; 25.1 ± 0.9 for WT and 16.0 ± 0.2 for KO in slow phase.)
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pgen.1004862.g001: Ca2+ kinetics of single twitches in FDB fibres from WT and Actn3 KO mice.A Superimposed representative twitch transients from an Actn3 KO and a WT fibre, showing faster [Ca2+]i decay in the KO fibre. Across our sample as a whole, there was no difference between WT and Actn3 KO fibres in the time taken to rise from 20% to 80% of peak (B). However, during decay, the rate constant of decay was significantly higher in Actn3 KO fibres than in WT fibres, both during the fast phase (C) and slow phase (D). (In B, C and D, n = 36 for WT and n = 31 for KO. In C and D, equivalent time constants, in ms, are: 2.2 ± 0.1 for WT and 1.6 ± 0.1 for KO in fast phase; 25.1 ± 0.9 for WT and 16.0 ± 0.2 for KO in slow phase.)

Mentions: As an overall indicator of potential alterations in Ca2+ handling by α-actinin-3-deficient muscle fibres, we examined Ca2+ kinetics of individual twitches in single FDB fibres from WT and Actn3 KO mice. Fig. 1 summarises the kinetics of Ca2+ transients elicited by a single action potential. Fig. 1A shows sample transients recorded during a single twitch in a WT fibre and a KO fibre. The superimposed recordings show a clear difference in the shape of the transients. Across our whole sample, there was no difference between WT and Actn3 KO fibres in the time taken to rise from 20% to 80% of maximum [Ca2+]i (Fig. 1B). However, the rate constant of decay was significantly higher in Actn3 KO fibres than in WT fibres, both during the fast phase (Fig. 1C) and slow phase (Fig. 1D) of [Ca2+]i decay. In some cases the resting [Ca2+]i was measured and was not significantly different between WT and Actn3 KO fibres (46 ± 5 nM for WT, n = 5; 47 ± 5 nM for KO, n = 10).


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)

Ca2+ kinetics of single twitches in FDB fibres from WT and Actn3 KO mice.A Superimposed representative twitch transients from an Actn3 KO and a WT fibre, showing faster [Ca2+]i decay in the KO fibre. Across our sample as a whole, there was no difference between WT and Actn3 KO fibres in the time taken to rise from 20% to 80% of peak (B). However, during decay, the rate constant of decay was significantly higher in Actn3 KO fibres than in WT fibres, both during the fast phase (C) and slow phase (D). (In B, C and D, n = 36 for WT and n = 31 for KO. In C and D, equivalent time constants, in ms, are: 2.2 ± 0.1 for WT and 1.6 ± 0.1 for KO in fast phase; 25.1 ± 0.9 for WT and 16.0 ± 0.2 for KO in slow phase.)
© Copyright Policy
Related In: Results  -  Collection

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

pgen.1004862.g001: Ca2+ kinetics of single twitches in FDB fibres from WT and Actn3 KO mice.A Superimposed representative twitch transients from an Actn3 KO and a WT fibre, showing faster [Ca2+]i decay in the KO fibre. Across our sample as a whole, there was no difference between WT and Actn3 KO fibres in the time taken to rise from 20% to 80% of peak (B). However, during decay, the rate constant of decay was significantly higher in Actn3 KO fibres than in WT fibres, both during the fast phase (C) and slow phase (D). (In B, C and D, n = 36 for WT and n = 31 for KO. In C and D, equivalent time constants, in ms, are: 2.2 ± 0.1 for WT and 1.6 ± 0.1 for KO in fast phase; 25.1 ± 0.9 for WT and 16.0 ± 0.2 for KO in slow phase.)
Mentions: As an overall indicator of potential alterations in Ca2+ handling by α-actinin-3-deficient muscle fibres, we examined Ca2+ kinetics of individual twitches in single FDB fibres from WT and Actn3 KO mice. Fig. 1 summarises the kinetics of Ca2+ transients elicited by a single action potential. Fig. 1A shows sample transients recorded during a single twitch in a WT fibre and a KO fibre. The superimposed recordings show a clear difference in the shape of the transients. Across our whole sample, there was no difference between WT and Actn3 KO fibres in the time taken to rise from 20% to 80% of maximum [Ca2+]i (Fig. 1B). However, the rate constant of decay was significantly higher in Actn3 KO fibres than in WT fibres, both during the fast phase (Fig. 1C) and slow phase (Fig. 1D) of [Ca2+]i decay. In some cases the resting [Ca2+]i was measured and was not significantly different between WT and Actn3 KO fibres (46 ± 5 nM for WT, n = 5; 47 ± 5 nM for KO, n = 10).

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