ACTN3 genotype influences muscle performance through the regulation of calcineurin signaling
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
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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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 3

Enhanced response to exercise training in KO mice.

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Enhanced response to exercise training in KO mice. Training increased ac...
Training increased activities of (A) HK, (B) CS, (C) SDH, and (D) BHAD in both WT and KO muscles. (E) Exercise training increased the level of COX IV in both WT and KO muscles, with KO muscles demonstrating higher levels of COX IV than WT in both untrained and trained states. (F) The CSA occupied by each fiber type is presented as a proportion of the overall muscle cross section. cKO muscles demonstrated 3.3% lower 2B CSA proportions (P = 0.093) and 2.5% higher 2X (P = 0.041) CSA proportions compared with cWT muscles. tWT muscles showed no significant alterations in CSA proportions for any fiber type compared with cWT muscles, while tKO muscles demonstrated significant decreases in 2B and increases in 2X CSA compared with cKO muscles (mean ± SEM; *P < 0.05; **P < 0.01; ***P < 0.001; †P < 0.05 for cWT versus cKO; #P < 0.05; §P < 0.01 for cKO versus tKO, Mann-Whitney U test; n = 6–7 muscles; greater than 5,000 fibers per muscle for all groups).