![]() Hence understanding the consequences of α-actinin-3 deficiency in humans may have wide-reaching implications.ĪCTN3 genotype has been linked with elite athletic performance in humans. Although 577XX genotype frequencies differ between human populations, it is estimated that 16% of individuals worldwide, or approximately one billion people, are deficient in α-actinin-3 ( 3). Individuals with two copies of the X allele ( ACTN3 577XX genotype) are completely deficient in α-actinin-3 ( 2). A common polymorphism in this gene, R577X, results in a premature stop codon in the place of an arginine residue at position 577. Α-Actinin-3 is a structural fast skeletal muscle protein encoded by the ACTN3 gene ( 1). We propose that the alteration in GPh activity in the absence of α-actinin-3 is a fundamental mechanistic link in the association between ACTN3 genotype and human performance. Finally, as GPh has been shown to regulate calcium handling, we examined calcium handling in KO mouse primary mouse myoblasts and find changes that may explain the slower contractile properties previously observed in these mice. We propose that the changes in glycogen metabolism underlie the downstream metabolic consequences of α-actinin-3 deficiency. The reduction in enzyme activity is accompanied by altered post-translational modification of GPh, suggesting that α-actinin-3 regulates GPh activity by altering its level of phosphorylation. Actn3 KO mice have higher muscle glycogen content and a 50% reduction in the activity of GPh. In this study, we demonstrated a link between α-actinin-3 and glycogen metabolism which may underlie the metabolic changes seen in the KO mouse. α-Actinins have been shown to interact with a number of muscle proteins including the key metabolic regulator glycogen phosphorylase (GPh). ACTN3 genotype is associated with human athletic performance and α-actinin-3 deficient mice have a shift in the properties of fast muscle fibres towards slower fibre properties, with increased activity of multiple enzymes in the aerobic metabolic pathway and slower contractile properties. Approximately one billion people worldwide are homozygous for a stop codon polymorphism in the ACTN3 gene (R577X) which results in complete deficiency of the fast fibre muscle protein α-actinin-3.
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