ACTN3genotype influences skeletal muscle mass regulation and response to dexamethasone

Abstract

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 and strength, increased risk of sarcopenia in the elderly, and altered response to muscle wasting induced by denervation and immobilisation. ACTN3 genotype is also a disease modifier for Duchenne muscular dystrophy (DMD), with α-actinin-3 deficiency associated with slower disease progression. Here we show that α-actinin-3 plays a key role in the regulation of protein synthesis and breakdown signalling in skeletal muscle, and its influence on muscle mass begins during early postnatal muscle development. Actn3 genotype also influences the skeletal muscle response to the glucocorticoid dexamethasone. Following acute dexamethasone exposure, transcriptomic analyses by RT-qPCR and RNA-sequencing show reduced atrophy signalling (Mstn, Tmem100, mRas, Fbxo32, Trim63) and anti-inflammatory response in α-actinin-3 deficient mice compared to wild-type. α-Actinin-3 deficiency also protects against muscle wasting following prolonged daily treatment with dexamethasone in female, but not male mice. In combination, these data suggest that ACTN3 R577X is a pharmacogenetic variant influencing the anti-inflammatory and muscle wasting response to glucocorticoid therapy.

Modern Insights into Muscle Glycogen Phosphorylase Activity

“…Animals and tissue collection The Actn3KO mouse line, initially created in this laboratory by introducing a neo cassette knockout onto an R129 background (23), has also been backcrossed onto a C57BL/6 line and used to investigate the effects of Actn3 deficiency in recent studies (24)(25)(26)(27). For this study, homozygous wildtype (WT) and Actn3 knockout (KO) mice were generated by het/het cross of Actn3 mice on a C57BL/6 background.…”