Institute for Neuroscience and Muscle Research

Lab head: Kathryn North
Location: Level 3, Research Building, Kids Research Institute, Children’s Hospital at Westmead

Understanding how a common null polymorphism in the ACTN3 gene influences muscle function

Lab members: 1 Laboratory Head, 6 Postdoctoral Fellows, 9 PhD students, 3 Undergraduate Research students, 1 Research Assistant.
Funding: NHMRC, ARC
Research approach equipment: We use mouse models of disease, tissue culture, isolated muscle physiology studies, viral gene delivery, molecular biology techniques, immunohistochemistry and biochemical approaches in our research.

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 and North KN (2007). Loss of ACTN3 gene function alters mouse muscle metabolism and shows evidence of positive selection in humans. Nature Genetics 39, 1261-1265

Quinlan KG, Seto JT, Turner N, Vandebrouck A, Floetenmeyer M, Macarthur DG, Raftery JM, Lek M, Yang N, Parton RG, Cooney GJ and North KN (2010).  Alpha-actinin-3 deficiency results in reduced glycogen phosphorylase activity and altered calcium handling in skeletal muscle.  Human Molecular Genetics, 19, 1335-1346

Seto JT, Lek M, Quinlan KG, Houweling PJ, Zheng XF, Garton F, MacArthur DG, Raftery JM, Garvey SM, Hauser MA, Yang N, Head SI and North KN (2011).  Deficiency of α-actinin-3 is associated with increased susceptibility to contraction-induced damage and skeletal muscle remodeling.  Human Molecular Genetics, 20, 2914-2927

A gene for speed: studying the role of α-actinin-3 in human muscle

Primary supervisor: Kathryn North

α-Actinin-3 is a skeletal muscle protein expressed primarily in fast-glycolytic fibres.  It is responsible for maintaining sarcomeric integrity by cross-linking other muscle proteins, such as skeletal actin. In 1999, we identified a common null polymorphism R577X in human α-actinin-3 (ACTN3); approximately 18% of Caucasians, or an estimated 1 billion people worldwide, are homozygous for the null X-allele which results in complete deficiency of α-actinin-3. Even though α-actinin-3 deficiency does not cause disease, we have found that its deficiency is detrimental to sprint/power performance in elite athletes.

An α-actinin-3 knockout mouse model (Actn3 KO) has since been developed. Actn3 KO mice show a shift towards slow muscle characteristics, which include resistance to fatigue, more oxidative/aerobic metabolism, reduced fast fibre size and significantly reduced muscle mass.

The aim of this project is to gain further understanding of the role α-actinin-3 plays in human muscle.  Using our Actn3 KO mouse we have obtained great insight into the mechanisms underlying the changes in muscle characteristics in the absence of α-actinin-3.  We have initiated an exciting new collaboration that has given us access to a cohort of muscle from a tightly controlled human group.  In this project we will be testing whether our mechanisms uncovered in mice apply to α-actinin-3 deficiency in humans.  The project will involve laboratory-based techniques such as immunohistochemistry, western blotting and quantitative real-time PCR (qPCR) and will be performed under the supervision of two laboratory-based post-doctoral fellows, Dr Peter Houweling and Dr Kate Quinlan.


Discipline: Pathology
Co-supervisors: Kate Quinlan, Peter Houweling
Keywords: protein structure/function, Athletic Performance, Genetics