PLoS ONE：中科院骨骼肌再生机制研究取得新成果

近日，《公共科学图书馆—综合》（PLoS ONE）在线发表了中科院上海生命科学研究院营养科学研究所应浩研究组与复旦大学附属儿科医院李西华博士在骨骼肌再生机制研究方面取得的新成果。

自2011年以来，应浩研究组和李西华博士合作致力于杜氏型肌营养不良（DMD）的诊断、治疗评价以及骨骼肌再生的生物学机制方面的研究。近期，应浩研究员指导的博士研究生张铎等人对骨骼肌早期再生过程中调控骨骼肌成肌细胞增殖的分子机制进行了研究探索。

他们利用多种骨骼肌再生小鼠模型和杜氏型肌营养不良患儿样本研究发现，miR-1/133在骨骼肌再生早期表达下调，而miR-1和miR-133通过各自的靶基因（Cyclin D1和Sp1）影响成肌细胞细胞周期，从而抑制成肌细胞增殖。进一步研究发现，生长因子FGF2以及p38信号通路是调控miR-1/133表达的上游信号分子和通路。这些研究结果很有可能为DMD治疗的研究提供新的思路和理论依据。

该项工作得到了中国科学院、科技部、国家自然科学基金委、上海市科委以及上海慈善协会和复旦大学附属儿科医院联合设立的DMD专项基金的经费支持。

杜氏型肌营养不良是一种随着年龄增长全身肌肉呈进行性消耗和运动功能逐渐丧失的遗传性肌肉疾病。患儿3-4岁开始出现步态异常，10-12岁起逐渐丧失行走能力，20-30岁间死于心肺功能衰竭，目前尚无有效根治手段。

Attenuation of p38-Mediated miR-1/133 Expression Facilitates Myoblast Proliferation during the Early Stage of Muscle Regeneration

Duo Zhang1, Xihua Li2, Chuchu Chen3, Yuyin Li1, Lei Zhao2, Yanyan Jing1, Wei Liu1, Xiaoyun Wang1, Ying Zhang1, Hongfeng Xia1, Yaning Chang3, Xiang Gao4, Jun Yan4,5, Hao Ying1*

Myoblast proliferation following myotrauma is regulated by multiple factors including growth factors, signal pathways, transcription factors, and miRNAs. However, the molecular mechanisms underlying the orchestration of these regulatory factors remain unclear. Here we show that p38 signaling is required for miR-1/133a clusters transcription and both p38 activity and miR-1/133 expression are attenuated during the early stage of muscle regeneration in various animal models. Additionally, we show that both miR-1 and miR-133 reduce Cyclin D1 expression and repress myoblast proliferation by inducing G1 phase arrest. Furthermore, we demonstrate that miR-133 inhibits mitotic progression by targeting Sp1, which mediates Cyclin D1 transcription, while miR-1 suppresses G1/S phase transition by targeting Cyclin D1. Finally, we reveal that proproliferative FGF2, which is elevated during muscle regeneration, attenuates p38 signaling and miR-1/133 expression. Taken together, our results suggest that downregulation of p38-mediated miR-1/133 expression by FGF2 and subsequent upregulation of Sp1/Cyclin D1 contribute to the increased myoblast proliferation during the early stage of muscle regeneration.