RARE MYOPATHIES AND EXPERIMENTAL APPROACHES - POSTER PRESENTATIONS G.P.125 ACTN3 genotype influences skeletal muscle performance through alterations in calcineurin signaling

Abstract

Abstract Approximately 1 billion people worldwide do not express the fast-twitch skeletal muscle fibre protein alpha-actinin-3 (a-act-3) due to homozygosity for a common null polymorphism in the ACTN3 gene. ACTN3 genotype influences skeletal muscle performance in elite athletes and in the general population; a-act-3 deficiency is associated with enhanced endurance capacity. Studies of the Actn3 KO mouse revealed that a-act-3 deficiency leads to a shift in fast muscle fibre contractile and metabolic properties towards those normally associated with slower muscle fibres. To gain mechanistic insights into these changes we performed a microarray and, interestingly, found that downstream targets of the calcineurin signalling pathway are altered in a-act-3 deficient muscle. We have now shown that the activity of calcineurin, which plays a critical role promoting fast-to-slow twitch fibre transition, is increased in KO mouse muscle, which likely accounts for the enhanced endurance performance in KO mice. We hypothesised that, due to the increased calcineurin activity, a-act-3 deficient muscle, may more readily adapt to physical demands that result in a fast-to-slow fibre conversion. KO mice demonstrate greater improvements in endurance performance following forced treadmill endurance training, associated with greater shifts in fast to slow fibre transition, increased fibre size and higher oxidative muscle metabolism compared to WT. We demonstrate that alpha-actinin-2 (a-act-2), which is upregulated in a-act-3 deficient muscle, has increased binding affinity for calsarcin-2, a key inhibitor of calcineurin activity. a-Act-2 competes with calsarcin-2 for binding to calcineurin, resulting in enhanced calcineurin signaling and the activation of the slow myogenic program. Our data provide, for the first time, a mechanistic explanation for the effects of ACTN3 genotype on skeletal muscle performance in elite athletes and adaptation to changing physical demands in the general population.