Department of Pathology, University of Texas Health Science Center, San Antonio, Texas, USA.
Physiol Genomics. 2012 Nov 1;44(21):1042-51. doi: 10.1152/physiolgenomics.00052.2012. Epub 2012 Sep 11.
MicroRNAs (miRNAs) regulate many biological processes including muscle development. However, little is known regarding miRNA regulation of muscle regeneration. Murine tibialis anterior muscle was evaluated after cardiotoxin-induced injury and used for global miRNA expression analysis. From day 1 through day 21 following injury, 298 miRNAs were significantly changed at least at one time point, including 86 miRNAs that were altered >10-fold compared with uninjured skeletal muscle. Temporal miRNA expression patterns included inflammation-related miRNAs (miR-223 and -147) that increased immediately after injury; this pattern contrasted to that of mature muscle-specific miRNAs (miR-1, -133a, and -499) that abruptly decreased following injury followed by upregulation in later regenerative events. Another cluster of miRNAs were transiently increased in the early days of muscle regeneration including miR-351, a miRNA that was also transiently expressed during myogenic progenitor cell (MPC) differentiation in vitro. Based on computational predictions, further studies demonstrated that E2f3 was a target of miR-351 in myoblasts. Moreover, knockdown of miR-351 expression inhibited MPC proliferation and promoted apoptosis during MPC differentiation, whereas miR-351 overexpression protected MPC from apoptosis during differentiation. Collectively, these observations suggest that miR-351 is involved in both the maintenance of MPC proliferation and the transition into differentiated myotubes. Thus, a novel, time-dependent sequence of molecular events during muscle regeneration has been identified; miR-351 inhibits E2f3 expression, a key regulator of cell cycle progression and proliferation, and promotes MPC proliferation and protects early differentiating MPC from apoptosis, important events in the hostile tissue environment after acute muscle injury.
微小 RNA（miRNA）调节许多生物学过程，包括肌肉发育。然而，关于 miRNA 对肌肉再生的调节作用知之甚少。使用心肌毒素诱导损伤后的鼠胫骨前肌进行全 miRNA 表达分析。损伤后第 1 天至第 21 天，298 个 miRNA 至少在一个时间点显著变化，其中 86 个 miRNA 的变化幅度超过未损伤骨骼肌的 10 倍。miRNA 表达的时间模式包括损伤后立即增加的炎症相关 miRNA（miR-223 和 miR-147）；与成熟的肌肉特异性 miRNA（miR-1、miR-133a 和 miR-499）形成对比，后者在损伤后突然减少，随后在后期再生事件中上调。另一群 miRNA 在肌肉再生的早期短暂增加，包括 miR-351，这是一种在体外成肌祖细胞（MPC）分化过程中也短暂表达的 miRNA。基于计算预测，进一步的研究表明，E2f3 是肌母细胞中 miR-351 的靶标。此外，miR-351 表达的敲低抑制 MPC 增殖并促进 MPC 分化中的细胞凋亡，而 miR-351 的过表达可防止分化过程中 MPC 的凋亡。总之，这些观察结果表明，miR-351 参与 MPC 的增殖维持和向分化的肌管过渡。因此，已经确定了肌肉再生过程中一个新的、依赖时间的分子事件序列；miR-351 抑制 E2f3 表达，E2f3 是细胞周期进程和增殖的关键调节因子，促进 MPC 增殖并保护早期分化的 MPC 免受凋亡，这是急性肌肉损伤后恶劣组织环境中的重要事件。
