MiR-206 Attenuates Denervation-Induced Skeletal Muscle Atrophy in Rats Through Regulation of Satellite Cell Differentiation via TGF-β1, Smad3, and HDAC4 Signaling.
MiR-206 Attenuates Denervation-Induced Skeletal Muscle Atrophy in Rats Through Regulation of Satellite Cell Differentiation via TGF-β1, Smad3, and HDAC4 Signaling.
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DOI：
10.12659/msm.897909
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发表时间：
2016-04-07
期刊：
影响因子：
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通讯作者：
Liang BS
中科院分区：
文献类型：
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作者：
Huang QK;Qiao HY;Fu MH;Li G;Li WB;Chen Z;Wei J;Liang BS
去神经诱导的骨骼肌萎缩导致显著的生化和生理变化，可能导致毁灭性的结果，包括死亡率增加。骨骼肌疾病的有效治疗方法目前尚不可用。肌肉特异性miRNA，如miR-206，在肌肉再生的调控中发挥重要作用。本研究的目的是检查miR-206治疗在骨骼肌萎缩早期变化期间的有益作用，并研究大鼠骨骼肌萎缩模型中的潜在信号通路。建立大鼠失神经支配骨骼肌萎缩模型。在有或没有TGF-β1抑制剂的情况下，大鼠中miRNA-206过表达。通过实时PCR和蛋白质印迹法测定HDAC 4、TGF-β1和Smad 3的mRNA和蛋白表达。测量腓肠肌横截面积和相对肌质量。免疫组化法检测MyoD 1、TGF-β1和Pax 7的表达。坐骨神经手术切断后，基本的肌肉特性，如相对肌肉重量，在2周内持续恶化。注射miR-206（30 μg/大鼠）减轻了肌肉特征的形态学和生理学恶化，有效地防止了纤维化，并抑制了TGF-β1和HDAC 4的表达，如在去神经支配后2周所评估的。此外，miR-206处理增加了分化中的（MyoD 1 +/Pax 7+）卫星细胞的数量，从而保护去神经肌肉免于萎缩。有趣的是，在TGF-β1/Smad 3轴的药理学阻断后，miR-206控制HDAC 4表达和减轻肌肉萎缩的能力减弱。TGF-β1/Smad 3信号通路是miR-206通过影响卫星细胞的增殖和分化来对抗骨骼肌萎缩的关键信号通路之一。miR-206可能是开发治疗早期失神经诱导的骨骼肌萎缩患者的新策略的潜在靶点。
Denervation-induced skeletal muscle atrophy results in significant biochemical and physiological changes potentially leading to devastating outcomes including increased mortality. Effective treatments for skeletal muscle diseases are currently not available. Muscle-specific miRNAs, such as miR-206, play an important role in the regulation of muscle regeneration. The aim of the present study was to examine the beneficial effects of miR-206 treatment during the early changes in skeletal muscle atrophy, and to study the underlying signaling pathways in a rat skeletal muscle atrophy model. The rat denervation-induced skeletal muscle atrophy model was established. miRNA-206 was overexpressed with or without TGF-β1 inhibitor in the rats. The mRNA and protein expression of HDAC4, TGF-β1, and Smad3 was determined by real-time PCR and western blot. The gastrocnemius muscle cross-sectional area and relative muscle mass were measured. MyoD1, TGF-β1, and Pax7 were determined by immunohistochemical staining. After sciatic nerve surgical transection, basic muscle characteristics, such as relative muscle weight, deteriorated continuously during a 2-week period. Injection of miR-206 (30 μg/rat) attenuated morphological and physiological deterioration of muscle characteristics, prevented fibrosis effectively, and inhibited the expression of TGF-β1 and HDAC4 as assessed 2 weeks after denervation. Moreover, miR-206 treatment increased the number of differentiating (MyoD1+/Pax7+) satellite cells, thereby protecting denervated muscles from atrophy. Interestingly, the ability of miR-206 to govern HDAC4 expression and to attenuate muscle atrophy was weakened after pharmacological blockage of the TGF-β1/Smad3 axis. TGF-β1/Smad3 signaling pathway is one of the crucial signaling pathways by which miR-206 counteracts skeletal muscle atrophy by affecting proliferation and differentiation of satellite cells. miR-206 may be a potential target for development of a new strategy for treatment of patients with early denervation-induced skeletal muscle atrophy.