Limits...
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.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.

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

Cold acclimatisation and thermogenesis in α-actinin-3-deficient fibres.The diagram shows the mechanisms by which a loss of α-actinin-3 from fast glycolytic muscle fibres could promote adaptation to cold environments. The increased Ca2+ leak (3), increased mitochondrial enzyme activity (4) and increased fatigue resistance (5) are all features of muscle fibres from mice exposed to prolonged cold, and hence α-actinin-3 deficiency can be said to “pre-acclimatise” muscles to cold environments. In addition, the increased pumping by the SERCA1 Ca2+-ATPase consumes ATP and generates heat (9), providing a thermogenic mechanism which would also enhance cold survival.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4295894&req=5

pgen.1004862.g006: Cold acclimatisation and thermogenesis in α-actinin-3-deficient fibres.The diagram shows the mechanisms by which a loss of α-actinin-3 from fast glycolytic muscle fibres could promote adaptation to cold environments. The increased Ca2+ leak (3), increased mitochondrial enzyme activity (4) and increased fatigue resistance (5) are all features of muscle fibres from mice exposed to prolonged cold, and hence α-actinin-3 deficiency can be said to “pre-acclimatise” muscles to cold environments. In addition, the increased pumping by the SERCA1 Ca2+-ATPase consumes ATP and generates heat (9), providing a thermogenic mechanism which would also enhance cold survival.

Mentions: In summary, we propose that α-actinin-3 deficiency adapts skeletal muscle to cold environments through the mechanisms depicted in Fig. 6. In this scheme, the primary event is a genetic deficiency in α-actinin-3 (1), which through as yet unidentified mechanisms results in an increase in the number of SERCA1 channels (2). These channels provide the pathway for an increased Ca2+ leak (3). The uptake of leaked Ca2+ into mitochondria causes an increase in mitochondrial enzyme activity (4). Mitochondrial enzyme activity can also be stimulated through increased activity of calcineurin (3a), which has been released from calsarcin-2 inhibition by the up-regulation of α-actinin-2 (2a). The increased oxidative capacity for ATP generation leads to increased fatigue resistance (5). The three characteristics of increased Ca2+ leak (3), increased mitochondrial enzyme activity (4) and increased fatigue resistance (5) are also found in the muscles of mice exposed to prolonged cold, and hence α-actinin-3-deficient muscle can be said to be “pre-acclimatised” to cold. In addition, these muscles contain a thermogenic mechanism. The increased Ca2+ leak is matched by an increased rate of pumping by the SERCA1 pumps (6), and the pumping is facilitated by the increased expression of the Ca2+-binding proteins, calsequestrin and sarcalumenin, within the SR lumen (7). The increased ATP hydrolysis (8) by the SERCA1 pumps generates heat (9). This cold-acclimatisation and thermogenesis in α-actinin-3-deficient muscle provides one possible explanation for the selective favouring of the ACTN3 577X polymorphism in populations living in cold environments during recent evolution, one of the very rare cases in the human genome of positive selection for a single-gene allele.


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)

Cold acclimatisation and thermogenesis in α-actinin-3-deficient fibres.The diagram shows the mechanisms by which a loss of α-actinin-3 from fast glycolytic muscle fibres could promote adaptation to cold environments. The increased Ca2+ leak (3), increased mitochondrial enzyme activity (4) and increased fatigue resistance (5) are all features of muscle fibres from mice exposed to prolonged cold, and hence α-actinin-3 deficiency can be said to “pre-acclimatise” muscles to cold environments. In addition, the increased pumping by the SERCA1 Ca2+-ATPase consumes ATP and generates heat (9), providing a thermogenic mechanism which would also enhance cold survival.
© Copyright Policy
Related In: Results  -  Collection

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

pgen.1004862.g006: Cold acclimatisation and thermogenesis in α-actinin-3-deficient fibres.The diagram shows the mechanisms by which a loss of α-actinin-3 from fast glycolytic muscle fibres could promote adaptation to cold environments. The increased Ca2+ leak (3), increased mitochondrial enzyme activity (4) and increased fatigue resistance (5) are all features of muscle fibres from mice exposed to prolonged cold, and hence α-actinin-3 deficiency can be said to “pre-acclimatise” muscles to cold environments. In addition, the increased pumping by the SERCA1 Ca2+-ATPase consumes ATP and generates heat (9), providing a thermogenic mechanism which would also enhance cold survival.
Mentions: In summary, we propose that α-actinin-3 deficiency adapts skeletal muscle to cold environments through the mechanisms depicted in Fig. 6. In this scheme, the primary event is a genetic deficiency in α-actinin-3 (1), which through as yet unidentified mechanisms results in an increase in the number of SERCA1 channels (2). These channels provide the pathway for an increased Ca2+ leak (3). The uptake of leaked Ca2+ into mitochondria causes an increase in mitochondrial enzyme activity (4). Mitochondrial enzyme activity can also be stimulated through increased activity of calcineurin (3a), which has been released from calsarcin-2 inhibition by the up-regulation of α-actinin-2 (2a). The increased oxidative capacity for ATP generation leads to increased fatigue resistance (5). The three characteristics of increased Ca2+ leak (3), increased mitochondrial enzyme activity (4) and increased fatigue resistance (5) are also found in the muscles of mice exposed to prolonged cold, and hence α-actinin-3-deficient muscle can be said to be “pre-acclimatised” to cold. In addition, these muscles contain a thermogenic mechanism. The increased Ca2+ leak is matched by an increased rate of pumping by the SERCA1 pumps (6), and the pumping is facilitated by the increased expression of the Ca2+-binding proteins, calsequestrin and sarcalumenin, within the SR lumen (7). The increased ATP hydrolysis (8) by the SERCA1 pumps generates heat (9). This cold-acclimatisation and thermogenesis in α-actinin-3-deficient muscle provides one possible explanation for the selective favouring of the ACTN3 577X polymorphism in populations living in cold environments during recent evolution, one of the very rare cases in the human genome of positive selection for a single-gene allele.

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.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.

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