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 1

Calcineurin signaling is increased in α-actinin-3–deficient muscles.

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Calcineurin signaling is increased in α-actinin-3–deficient muscles. (A)...
(A) Muscles of KO mice on a C57BL/6J background showed a 1.3-fold increase in RCAN1-4 protein expression compared with WT muscles, suggesting increased calcineurin activity (P = 0.057; n = 3–4 for both groups). (B) In exercised mice on a 129 background, RCAN1-4 was 2.9-fold upregulated in the KO group (P = 0.004; n = 6 for both groups). (C) Direct assays of calcineurin activity confirmed a 1.9-fold increase in calcineurin signaling in exercised KO muscles (P = 0.093; n = 6 for both groups). (D) Calsarcin-2 expression was similar between WT and KO muscles (mean ± SEM; **P < 0.01, Mann-Whitney U test). In B and D, the lanes were run on the same gel but were noncontiguous.