Molecular mechanisms of alpha-actinin-3 deficiency on skeletal muscle functions

Summary

An investigation into the effects of ACTN3 deficiency on human athletic performance and metabolism via the use of a knockout mouse model.

Supervisor(s)

Professor Kathryn North

Research Location

Institute for Neuromuscular Research, Neurogenetics Research Unit, The Children's Hospital at Westmead Clinical School

Program Type

Masters/PHD

Synopsis

The human ACTN3 gene encodes the protein a-actinin-3, a component of the contractile apparatus in fast skeletal muscle fibers. Its primary function is to anchor actin-thin filaments in order to maintain the integrity of the muscle contractile apparatus. We have identified a common null polymorphism in the ACTN3 gene (R577X), which results in a premature stop codon and consequently over one billion people worldwide are deficient in α-actinin-3. We have demonstrated that α-actinin-3 deficiency is detrimental to athletic sprint/power performance, but it may provide a benefit to endurance athletes. We have generated an Actn3 knock-out (KO) mouse model to mimic ACTN3 deficiency in humans. Intriguingly, Actn3 null mice are able to run a greater distance than wild type litter mates before reaching exhaustion. The muscle mass and fast-fiber cross-sectional area are reduced in KO mice. In more detailed analysis we have shown that the contractile properties of fast-twitch muscles in KO mice shift to a more slower phenotype - they have a decreased contraction speed and an increased fatigue resistance, and their energy metabolisms shift towards a more aerobic and oxidative state. In essence, it appears that α-actinin-3 deficiency results in the muscle being essentially "pre-trained" for endurance performance. We are now examining the effects of α-actinin-3 deficiency in exercise and training, in aged mice, and in modification of other muscle diseases. Further studies aim to unravel the molecular pathways which are altered due to the lack of α-actinin-3 in skeletal muscle fibers.

Keywords

Genetics, molecular biology, animal model, physiology, exercise and performance, skeletal muscle functions, Genetic disorders, Movement disorders, Human body, Movement

Opportunity ID

The opportunity ID for this research opportunity is: 226

Other opportunities with Professor Kathryn North

• α-Actinin and Skeletal Muscle performance: Role of α-actinin-3 in muscle performance, metabolism, and disease
• Dysferlin and defective membrane repair in muscular dystrophy