Using AAV vectors expressing the β2-adrenoceptor or associated Gα proteins to modulate skeletal muscle mass and muscle fibre size.
Using AAV vectors expressing the β2-adrenoceptor or associated Gα proteins to modulate skeletal muscle mass and muscle fibre size.
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DOI：
10.1038/srep23042
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发表时间：
2016-03-14
影响因子：
4.6
通讯作者：
Gregorevic P
中科院分区：
文献类型：
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作者：
Hagg A;Colgan TD;Thomson RE;Qian H;Lynch GS;Gregorevic P
合成代谢β2-肾上腺素能受体（β2-AR）激动剂已被提议作为治疗肌肉萎缩的药物，但对可能的脱靶效应的担忧阻碍了它们的使用。我们研究了β2-AR介导的信号是否可以通过基因传递到靶组织来调节骨骼肌，从而避免β2-AR激动剂的风险。在小鼠中，肌内注射表达β2-AR的重组腺相关病毒载体（rAAV载体），在4周内使肌肉质量增加了20%。这种肥厚反应与用β2-AR激动剂福莫特罗治疗4周的反应相当，并且不会被mTOR抑制所消除。抑制性（Gαi2）和刺激性（GαsL） g蛋白亚基表达的增加分别引起肌肉质量的轻微萎缩和增生性变化。此外，g - αi2过表达可阻止AAV:β2-AR介导的肥厚。引入非肌肉Gαs亚型后，GαsXL引起的肥厚与AAV:β2-AR引起的肥厚相当。此外，g - α sxl基因的传递能够诱导缺乏功能性β1-和β2- ar的小鼠肌肉肥大。这些发现表明，靶向β2-AR通路的基因治疗干预可以独立于配体给药促进骨骼肌肥大，并强调了在疾病环境中潜在调节肌肉质量的新方法。
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.