title: Using AAV vectors expressing the β2-adrenoceptor or associated Gα proteins to modulate skeletal muscle mass and muscle fibre size.
abstract: Anabolic β2-adrenoceptor (β2-AR) agonists have been proposed as therapeutics for treating muscle wasting but concerns regarding possible off-target effects have hampered their use. We investigated whether β2-AR-mediated signalling could be modulated in skeletal muscle via gene delivery to the target tissue, thereby avoiding the risks of β2-AR agonists. In mice, intramuscular administration of a recombinant adeno-associated virus-based vector (rAAV vector) expressing the β2-AR increased muscle mass by >20% within 4 weeks. This hypertrophic response was comparable to that of 4 weeks' treatment with the β2-AR agonist formoterol, and was not ablated by mTOR inhibition. Increasing expression of inhibitory (Gαi2) and stimulatory (GαsL) G-protein subunits produced minor atrophic and hypertrophic changes in muscle mass, respectively. Furthermore, Gαi2 over-expression prevented AAV:β2-AR mediated hypertrophy. Introduction of the non-muscle Gαs isoform, GαsXL elicited hypertrophy comparable to that achieved by AAV:β2-AR. Moreover, GαsXL gene delivery was found to be capable of inducing hypertrophy in the muscles of mice lacking functional β1- and β2-ARs. These findings demonstrate that gene therapy-based interventions targeting the β2-AR pathway can promote skeletal muscle hypertrophy independent of ligand administration, and highlight novel methods for potentially modulating muscle mass in settings of disease.
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, 3004, Australia.|Dept. of Physiology, The University of Melbourne, Melbourne, 3010, Australia.
authors.forename: Adam
authors.initials: A
authors.lastname: Hagg
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, 3004, Australia.|Dept. of Physiology, The University of Melbourne, Melbourne, 3010, Australia.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Colgan
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, 3004, Australia.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Thomson
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, 3004, Australia.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Qian
authors.affiliation: Dept. of Physiology, The University of Melbourne, Melbourne, 3010, Australia.
authors.forename: Gordon S
authors.initials: GS
authors.lastname: Lynch
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, 3004, Australia.|Dept. of Physiology, The University of Melbourne, Melbourne, 3010, Australia.|Dept. of Biochemistry and Molecular Biology, Monash University, Clayton, 3800, Australia.|Department of Neurology, University of Washington School of Medicine, Seattle, 98195, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Gregorevic
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D000229:Dependovirus / Q000235:genetics; D000068759:Formoterol Fumarate / Q000494:pharmacology; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000235:genetics* / Q000378:metabolism; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics* / Q000378:metabolism; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics; D006984:Hypertrophy / Q000235:genetics; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D024462:Myosin Type II / Q000378:metabolism; D009929:Organ Size / Q000235:genetics; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics* / Q000378:metabolism
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D018343:Receptors, Adrenergic, beta-2; D024462:Myosin Type II; D051960:GTP-Binding Protein alpha Subunit, Gi2; D019205:GTP-Binding Protein alpha Subunits, Gs; D000068759:Formoterol Fumarate