The Effect of ACTN3 Gene Doping on Skeletal Muscle Performance
| Autor: | Chrystal F. Tiong, Nan Yang, Stewart I. Head, Peter J. Houweling, Lyra R. Meehan, Marshall W. Hogarth, Fleur C. Garton, Paul Gregorevic, Stephen Leslie, Jane T. Seto, Fiona Lee, Damjan Vukcevic, Kathryn N. North, Diana Zannino, Kelly N. Roeszler, Monkol Lek |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Gene isoform Heterozygote medicine.medical_specialty Muscle Fibers Skeletal Down-Regulation Actinin 030105 genetics & heredity Biology Gene dosage Article 03 medical and health sciences Gene doping Internal medicine Genetics medicine Animals Humans Anaerobiosis Allele Muscle Skeletal Genetics (clinical) Muscle fatigue Calcineurin Homozygote Skeletal muscle Organ Size Dependovirus Mice Inbred C57BL 030104 developmental biology Endocrinology medicine.anatomical_structure Animals Newborn Athletes Muscle Fatigue Knockout mouse Oxidation-Reduction Genome-Wide Association Study |
| Zdroj: | The American Journal of Human Genetics. 102:845-857 |
| ISSN: | 0002-9297 |
| Popis: | Loss of expression of ACTN3, due to homozygosity of the common null polymorphism (p.Arg577X), is underrepresented in elite sprint/power athletes and has been associated with reduced muscle mass and strength in humans and mice. To investigate ACTN3 gene dosage in performance and whether expression could enhance muscle force, we performed meta-analysis and expression studies. Our general meta-analysis using a Bayesian random effects model in elite sprint/power athlete cohorts demonstrated a consistent homozygous-group effect across studies (per allele OR = 1.4, 95% CI 1.3-1.6) but substantial heterogeneity in heterozygotes. In mouse muscle, rAAV-mediated gene transfer overexpressed and rescued α-actinin-3 expression. Contrary to expectation, in vivo "doping" of ACTN3 at low to moderate doses demonstrated an absence of any change in function. At high doses, ACTN3 is toxic and detrimental to force generation, to demonstrate gene doping with supposedly performance-enhancing isoforms of sarcomeric proteins can be detrimental for muscle function. Restoration of α-actinin-3 did not enhance muscle mass but highlighted the primary role of α-actinin-3 in modulating muscle metabolism with altered fatiguability. This is the first study to express a Z-disk protein in healthy skeletal muscle and measure the in vivo effect. The sensitive balance of the sarcomeric proteins and muscle function has relevant implications in areas of gene doping in performance and therapy for neuromuscular disease. |
| Databáze: | OpenAIRE |
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