Myostatin is a negative regulator of muscle mass and its inhibition represents a promising strategy for the treatment of muscle disorders and type 2 diabetes. However, there is currently no clinically effective myostatin inhibitor, and therefore novel methods are required. We evaluated the use of antisense phosphorodiamidate morpholino oligomers (PMO) to reduce myostatin expression in skeletal muscle and measured their effects on muscle mass and glucose uptake. C57/Bl6 mice received intramuscular or intravenous injections of anti-myostatin PMOs. Repeated intramuscular administration lead to a reduction in myostatin transcript levels (~ 20–40%), and an increase in muscle mass in chow and high-fat diet (HFD)-fed mice, but insulin-stimulated glucose uptake was reduced in PMO-treated muscles of HFD-fed mice. Five weekly intravenous administrations of 100 nmol PMO did not reduce myostatin expression, and therefore had no significant physiological effects. Unexpectedly, exon skipping levels were higher after intramuscular administration of PMO in HFD- than chow-fed mice. These results suggest that a modest PMO-induced reduction in myostatin transcript levels is sufficient to induce an increase in muscle mass, but that a greater degree of inhibition may be required to improve muscle glucose uptake.

肌肉生长抑制素是肌肉质量的负调节剂，其抑制是治疗肌肉疾病和 2 型糖尿病的一种有前景的策略。然而，目前还没有临床有效的肌生长抑制素抑制剂，因此需要新的方法。我们评估了使用反义磷酰二胺吗啉代寡聚体 (PMO) 来减少骨骼肌中肌生长抑制素的表达，并测量它们对肌肉质量和葡萄糖摄取的影响。C57/Bl6 小鼠接受肌内或静脉内注射抗肌生长抑制素 PMO。重复肌肉注射导致肌肉生长抑制素转录水平降低（约 20-40%），饲料和高脂肪饮食 (HFD) 喂养的小鼠肌肉质量增加，但胰岛素刺激的葡萄糖摄取在 PMO-经处理的 HFD 喂养小鼠的肌肉。100 nmol PMO 每周静脉注射五次不会降低肌肉生长抑制素的表达，因此没有显着的生理影响。出乎意料的是，与饲料喂养的小鼠相比，在 HFD 中肌内注射 PMO 后外显子跳跃水平更高。这些结果表明，PMO 诱导的肌肉生长抑制素转录水平的适度降低足以诱导肌肉质量的增加，但可能需要更大程度的抑制来改善肌肉葡萄糖摄取。