ACTN3 genotype influences skeletal muscle mass regulation and response to dexamethasone

Homozygosity for the common ACTN3 null polymorphism (ACTN3 577X) results in alpha-actinin-3 deficiency in similar to 20% of humans worldwide and is linked to reduced sprint and power performance in both elite athletes and the general population. alpha-Actinin-3 deficiency is also associated with reduced muscle mass, increased risk of sarcopenia, and altered muscle wasting response induced by denervation and immobilization. Here, we show that alpha-actinin-3 plays a key role in the regulation of protein synthesis and breakdown signaling in skeletal muscle and influences muscle mass from early postnatal development. We also show that alpha-actinin-3 deficiency reduces the atrophic and anti-inflammatory response to the glucocorticoid dexamethasone in muscle and protects against dexamethasone-induced muscle wasting in female but not male mice. The effects of alpha-actinin-3 deficiency on muscle mass regulation and response to muscle wasting provide an additional mechanistic explanation for the positive selection of the ACTN3 577X allele in recent human history.

Automated summary

Homozygosity for the common ACTN3 null polymorphism leads to deficiency in alpha-actinin-3, impacting sprint and power performance. Alpha-actinin-3 plays a critical role in regulating protein synthesis and breakdown in skeletal muscle, affecting muscle mass development. Deficiency in alpha-actinin-3 reduces the muscle wasting response to glucocorticoid dexamethasone, providing insights into the positive selection of the ACTN3 577X allele.