ACTN3 genotype influences skeletal muscle mass regulation and response to dexamethasone.

Homozygosity for the common ACTN3 null polymorphism (ACTN3 577X) results in α-actinin-3 deficiency in ~20% of humans worldwide and is linked to reduced sprint and power performance in both elite athletes and the general population. α-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 α-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 α-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 α-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.

Loss of α-actinin-3 during human evolution provides superior cold resilience and muscle heat generation.

The protein α-actinin-3 expressed in fast-twitch skeletal muscle fiber is absent in 1.5 billion people worldwide due to homozygosity for a nonsense polymorphism in ACTN3 (R577X). The prevalence of the 577X allele increased as modern humans moved to colder climates, suggesting a link between α-actinin-3 deficiency and improved cold tolerance. Here, we show that humans lacking α-actinin-3 (XX) are superior in maintaining core body temperature during cold-water immersion due to changes in skeletal muscle thermogenesis. Muscles of XX individuals displayed a shift toward more slow-twitch isoforms of myosin heavy chain (MyHC) and sarcoplasmic reticulum (SR) proteins, accompanied by altered neuronal muscle activation resulting in increased tone rather than overt shivering. Experiments on Actn3 knockout mice showed no alterations in brown adipose tissue (BAT) properties that could explain the improved cold tolerance in XX individuals. Thus, this study provides a mechanism for the positive selection of the ACTN3 X-allele in cold climates and supports a key thermogenic role of skeletal muscle during cold exposure in humans.