Metabolic consequences of α-actinin-3 deficiency – more than a structural muscle protein!

P.J. Houweling,¹ Y. Berman,¹ N. Turner,² K.G. Quinlan,¹ N. Yang,¹ G. Cooney² and K.N. North,¹ ¹The Institute for Neuroscience and Muscle Research, Children’s Hospital Westmead, Westmead, NSW 2145, Australia and ²Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.

Homozygosity for a common null polymorphism (R577X) in the gene ACTN3 results in absence of the fast muscle fibre protein α-actinin-3 in approximately 18% of the general population. ACTN3 genotype has been shown to influence elite and general athletic performance, muscle mass and strength (Yang et al., 2003). Specifically α-actinin-3 deficient fast muscle fibres show a shift towards an oxidative phenotype. While this favors endurance, the trade-off is that the muscle cannot generate the rapid contractions needed to excel in power/sprint activities. Furthermore, preliminary data from five human cohorts has demonstrated that α-actinin-3 deficiency is associated with a reduced frequency of obesity, altered glucose and insulin homeostasis along with an increased risk of developing type-2 diabetes when obese.

An Actn3 knockout (KO) mouse model has been established to examined muscle performance and metabolism (MacArthur & North, 2007; MacArthur et al., 2007,2008). This model has shown that α-actinin-3 plays a role in the post-translational regulation of glycogen phosphorylase, and α-actinin-3 deficiency leads to a significantly reduced capacity to use glycogen as an energy source (Quinlan et al., 2010). We have now determined that the absence of α-actinin-3 also influences glucose metabolism and alters weight gain on a high fat diet (HFD). Specifically KO mice show improved glucose clearance at baseline and resistance to weight gain following HFD. We have now begun to identify the molecular pathways involved in this response – highlighting α-actinin-3 as an important genetic regulator of key metabolic signaling pathways AMPK and calcineurin.

α-Actinin-3 is commonly considered to be a structural muscle protein. Through this research we have shown a prominent effect in skeletal muscle energy metabolism. The existence of a common genetic variant that affects the structural and metabolic function of muscle has important implications for health – in particular regarding weight gain, obesity, type-2 diabetes and metabolic disease.

Yang N, MacArthur DG, Gulbin JP, Hahn AG, Beggs AH, Easteal S, North K. (2003) ACTN3 genotype is associated with human elite athletic performance. American Journal of Human Genetics 73: 627-31.

MacArthur DG, North KN. (2007) ACTN3: A genetic influence on muscle function and athletic performance. Exercise and Sport Sciences Reviews 35: 30-4.

MacArthur DG, Seto JT, Chan S, Quinlan KG, Raftery JM, Turner N, Nicholson MD, Kee AJ, Hardeman EC, Gunning PW, Cooney GJ, Head SI, Yang N, North KN. (2008) An Actn3 knockout mouse provides mechanistic insights into the association between α-actinin-3 deficiency and human athletic performance. Human Molecular Genetics 17: 1076-86.

MacArthur DG, Seto JT, Raftery JM, Quinlan KG, Huttley GA, Hook JW, Lemckert FA, Kee AJ, Edwards MR, Berman Y, Hardeman EC, Gunning PW, Easteal S, Yang N, North KN. (2007) Loss of ACTN3 gene function alters mouse muscle metabolism and shows evidence of positive selection in humans. Nature Genetics 39: 1261-5.

Quinlan KG, Seto JT, Turner N, Vandebrouck A, Floetenmeyer M, Macarthur DG, Raftery JM, Lek M, Yang N, Parton RG, Cooney GJ, North KN. (2010) α-Actinin-3 deficiency results in reduced glycogen phosphorylase activity and altered calcium handling in skeletal muscle. Human Molecular Genetics 19: 1335-46.

Research Funding: National Health and Medical Research Council of Australia (NHMRC).