A gene for speed: The influence of ACTN3 on muscle performance in health and disease

α-Actinin-3 is a fast fibre Z-line protein that interacts with a wide array of structural, metabolic and signalling proteins. A common ACTN3 null polymorphism (R577X) is the most widely studied and best replicated genetic variant known to influence the skeletal muscle performance. ACTN3 genotype contributes ~2.5% of the variance in human muscle strength and exercise training response, is a risk factor for falling in the elderly and a genetic modifier of muscle disorders such as Duchenne muscular dystrophy. Homozygosity for the null allele (ACTN3 577XX) results in α-actinin-3 deficiency in ~20% of humans worldwide and is associated with reduced sprint and power performance in elite athletes and non-athletes. Actn3 KO mice demonstrate reduced strength and muscle mass, and enhanced endurance performance, similar to ACTN3 577XX humans. We have demonstrated in mice and humans that α-actinin-3 deficiency results in a shift in fast fibre metabolic and contractile properties towards those of slower oxidative fibres – explaining the detrimental effect on sprint performance and enhanced endurance performance and training response. Using a systems biology approach, we have shown that α-actinin-3 deficiency alters the binding affinities of a key group of structural, signalling and metabolic proteins at the Z-line. This, in turn, leads to a shift towards slow oxidative metabolism in the skeletal muscle through a combination of (i) decreased activity of glycogen phosphorylase; (ii) enhanced calcineurin activity; and (iii) changes in Ca2+ handling properties. We have recently demonstrated that ACTN3 genotype influences muscle mass through direct regulation of the PI3K/Akt/mTOR pathway and androgen receptor signalling. We are currently studying the effect of ACTN3 genotype on common causes of muscle wasting, and response to treatment with hypertrophic agents.