Publications

Abstract

alpha-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 alpha-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 alpha-actinin-3 deficiency results in increased calcineurin activity in mouse and human skeletal muscle and enhanced adaptive response to endurance training. alpha-Actinin-2, which is differentially expressed in alpha-actinin-3-deficient muscle, has higher binding affinity for calsarcin-2, a key inhibitor of calcineurin activation. We have further demonstrated that alpha-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 alpha-actinins play a role in the regulation of calcineurin signaling.