|Title:||The role of a-actinin-3 in muscle adaptation to changing physical demands and the molecular mechanisms involved|
|Publisher:||University of Sydney.|
Faculty of Medicine.
Paediatrics & Child Health.
Children's Hospital at Westmead.
|Abstract:||A common null polymorphism (R577X) in the ACTN3 gene results in complete absence of α-actinin-3 in ~16% of the world’s population. α-Actinin-3 deficiency is detrimental to performance in elite sprint athletes the mechanisms altering muscle performance have been modelled in an Actn3 KO mouse. KO muscle has smaller fast 2B fibres (where Actn3 is predominantly expressed), reduced absolute force, increased oxidative enzyme activity and enhanced calcineurin signalling. We examined the molecular mechanisms of α-actinin-3 deficiency on muscle disuse adaptation. KO mice demonstrated reduced muscle atrophy in fast 2B fibres and an enhanced propensity for MyHC isoforms to shift towards a slower, more oxidative profile. To investigate ACTN2 vs. ACTN3 molecular differences we performed an intramuscular gene delivery. Remarkably, a tight internal regulation of α-actinins existed, to show delivery and increase of α-actinin-3 resulted in reduced endogenous levels of α-actinin-2, and vice versa. Interestingly, while intramuscular ACTN3 delivery to KO muscle rescued some phenotypes, we found over-expression of ACTN2 and ACTN3 resulted in a degeneration/regenerative response with increased internalised nuclei and altered myofibrillar proteins. These studies also identified altered calcineurin signalling responsiveness and overall, demonstrated independent molecular mechanisms of each sarcomeric α-actinin, critical for muscle structure, metabolism and adaptation.|
|Access Level:||Access is restricted to staff and students of the University of Sydney . UniKey credentials are required. Non university access may be obtained by visiting the University of Sydney Library.|
|Rights and Permissions:||The author retains copyright of this thesis. It may only be used for the purposes of research and study. It must not be used for any other purposes and may not be transmitted or shared with others without prior permission.|
|Type of Work:||PhD Doctorate|
|Type of Publication:||Doctor of Philosophy Ph.D.|
|Appears in Collections:||Sydney Digital Theses (University of Sydney Access only)|
|GARTON Fleur - Final Thesis.pdf||Thesis||7.52 MB||Adobe PDF|
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