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.Introduction α-Actinin-3 is one of the major components of the skeletal muscle Z-disk in fast-twitch muscle fibers (1) and interacts with multiple structural, metabolic, and signaling proteins (2, 3). Homozygosity for a common nonsense polymorphism in the ACTN3 gene (R577X) results in complete α-actinin-3 deficiency in an estimated 16% of the global population (4) and is associated with variations in human muscle performance. The ACTN3 577XX-null genotype is markedly underrepresented in elite sprint and power athletes (5-9) and is associated with reduced muscle strength and sprint performance in nonathlete cohorts (10-13), suggesting that α-actinin-3 deficiency has a detrimental effect on the optimal function of fast muscle fibers. In contrast, the ACTN3 577XX genotype is overrepresented in elite endurance athlete cohorts (5, 14, 15), suggesting a beneficial effect on endurance capacity. Recent studies in athletes and nonathletes further suggest that the ACTN3 genotype influences the adaptive response of skeletal muscle to exercise training (10, 16).The Actn3 KO mouse model mimics the phenotypic effects of α-actinin-3 deficiency in humans (17). The closely related sarcomeric isoform α-actinin-2 compensates for the absence of α-actinin-3 and is expressed in all fiber types in Actn3 KO mice, similarly to ACTN3 577XX humans. Compared with WT mice, Actn3 KO mice have substantially lower grip strength, increased recovery from fatigue, and enhanced endurance exercise performance associated with increased levels of glycogen and a shift in fast muscle fiber properties toward a slow-twitch, oxidative phenotype, without

The sarcomeric cytoskeleton: from molecules to motion

“…Whether the sprint performance advantage of wild-type ACTN3 carriers is due to subtle differences in molecular mechanical properties or in the interaction with any of the many α-actinin interacting proteins that link to cellular signalling and metabolic pathways (Djinovic-Carugo et al, 2002;Lange et al, 2006;Linke and Kruger, 2010;Sanger et al, 2010) is currently unclear. However, these observations underscore the role of the sarcomeric cytoskeleton as not only a passive scaffold but also a determinant of muscle performance and metabolism (Berman and North, 2010), which has recently been linked to differential transcriptional regulation by calcineurin via calsarcin-2/myozenin-1/FATZ-1 at the α-actinin scaffold (Seto et al, 2013). Form and function seem to be truly interdependent.…”

Effects of aging, exercise, and disease on force transfer in skeletal muscle

“…In healthy individuals of European decent, ϳ18% are deficient in ACNT3 due to a common nonsense polymorphism in the ACTN3 gene, R577X (76). The early identification of this polymorphism has led to intense investigation as to the role of ACTN3 deficiency in muscle damage, strength/power, and human performance (15,19,56,100,110,119).…”

Alpha-actinin-3 R577X Polymorphism Profile of Turkish Professional Hip-Hop and Latin Dancers

“…It is difficult to explain dancing performance and its association with RX genotype, but we may speculate on the advantages of this deficiency. A previous study showed that deficiency in actn3 protein resulted in increased calcineurin metabolism of skeletal muscle and an enhanced adaptive response to endurance training (12). This finding may help us to explain why X allele and individuals with XX or RX genotype has predisposition to aerobic performance.…”