Using AAV vectors expressing the beta 2-adrenoceptor or associated G alpha proteins to modulate skeletal muscle mass and muscle fibre size

作者：Hagg Adam; Colgan Timothy D; Thomson Rachel E; Qian Hongwei; Lynch Gordon S; Gregorevic Paul^*

来源：Scientific Reports, 2016, 6(1): 23042.

DOI：10.1038/srep23042

Anabolic beta(2)-adrenoceptor (beta(2)-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 beta(2)-AR-mediated signalling could be modulated in skeletal muscle via gene delivery to the target tissue, thereby avoiding the risks of beta(2)-AR agonists. In mice, intramuscular administration of a recombinant adeno-associated virus-based vector (rAAV vector) expressing the beta(2)-AR increased muscle mass by >20% within 4 weeks. This hypertrophic response was comparable to that of 4 weeks' treatment with the beta(2)-AR agonist formoterol, and was not ablated by mTOR inhibition. Increasing expression of inhibitory (G alpha i2) and stimulatory (G alpha sL) G-protein subunits produced minor atrophic and hypertrophic changes in muscle mass, respectively. Furthermore, G alpha i2 over-expression prevented AAV:beta(2)-AR mediated hypertrophy. Introduction of the non-muscle G alpha s isoform, G alpha sXL elicited hypertrophy comparable to that achieved by AAV: beta(2)-AR. Moreover, G alpha sXL gene delivery was found to be capable of inducing hypertrophy in the muscles of mice lacking functional beta(1)- and beta(2)-ARs. These findings demonstrate that gene therapy-based interventions targeting the beta(2)-AR pathway can promote skeletal muscle hypertrophy independent of ligand administration, and highlight novel methods for potentially modulating muscle mass in settings of disease.

• 出版日期2016-3-14