ACTN3 genotype influences muscle performance through the regulation of calcineurin signaling
Jane T. Seto, … , Nan Yang, Kathryn N. North
Jane T. Seto, … , Nan Yang, Kathryn N. North
Published September 16, 2013
Citation Information: J Clin Invest. 2013;123(10):4255-4263. https://doi.org/10.1172/JCI67691.
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Research Article Muscle biology

ACTN3 genotype influences muscle performance through the regulation of calcineurin signaling

Abstract

α-Actinin-3 deficiency occurs in approximately 16% of the global population due to homozygosity for a common nonsense polymorphism in the ACTN3 gene. Loss of α-actinin-3 is associated with reduced power and enhanced endurance capacity in elite athletes and nonathletes due to “slowing” of the metabolic and physiological properties of fast fibers. Here, we have shown that α-actinin-3 deficiency results in increased calcineurin activity in mouse and human skeletal muscle and enhanced adaptive response to endurance training. α-Actinin-2, which is differentially expressed in α-actinin-3–deficient muscle, has higher binding affinity for calsarcin-2, a key inhibitor of calcineurin activation. We have further demonstrated that α-actinin-2 competes with calcineurin for binding to calsarcin-2, resulting in enhanced calcineurin signaling and reprogramming of the metabolic phenotype of fast muscle fibers. Our data provide a mechanistic explanation for the effects of the ACTN3 genotype on skeletal muscle performance in elite athletes and on adaptation to changing physical demands in the general population. In addition, we have demonstrated that the sarcomeric α-actinins play a role in the regulation of calcineurin signaling.

Authors

Jane T. Seto, Kate G.R. Quinlan, Monkol Lek, Xi Fiona Zheng, Fleur Garton, Daniel G. MacArthur, Marshall W. Hogarth, Peter J. Houweling, Paul Gregorevic, Nigel Turner, Gregory J. Cooney, Nan Yang, Kathryn N. North

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Figure 2

Endurance performance and grip strength of WT and KO mice after endurance training.

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Endurance performance and grip strength of WT and KO mice after enduranc...
(A) The endurance performance of untrained control WT (cWT) and control KO mice (cKO) were not significantly different at 15 to 16 weeks of age, however, the endurance performance of KO mice was significantly greater than WT mice after training. Trained WT mice (tWT) ran twice the distance of the cWT mice, while trained KO mice (tKO) ran 3.3 times the distance of untrained KO mice. (B) No significant increase in grip strength was detected in either WT or KO mice with endurance training. WT mice demonstrated greater grip strength than KO mice in both the untrained and trained groups (mean ± SEM; *P < 0.05 for WT versus tKO; **P < 0.01, Mann-Whitney U test; n = 6–8 for all groups).