Local applications of myostatin-siRNA with atelocollagen increase skeletal muscle mass and recovery of muscle function.
Local applications of myostatin-siRNA with atelocollagen increase skeletal muscle mass and recovery of muscle function.
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DOI：
10.1371/journal.pone.0064719
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Tanaka E
中科院分区：
文献类型：
--
作者：
Kawakami E;Kawai N;Kinouchi N;Mori H;Ohsawa Y;Ishimaru N;Sunada Y;Noji S;Tanaka E
越来越多的证据表明，小干扰RNA（siRNA）可以促进哺乳动物细胞中的基因沉默，而不诱导干扰素合成或非特异性基因抑制。近年来，人们开发了许多针对致病或促病基因的高度特异性siRNA。在这项研究中，我们评估了去端胶原（ATCOL）介导的siRNA靶向肌肉生长抑制素（Mst），骨骼肌生长的负调节剂，到肌营养不良模型小鼠的骨骼肌的有效性。我们将含有肌生长抑制素-siRNA和ATCOL的纳米颗粒复合物（Mst-siRNA/ATCOL）注射到突变小窝蛋白-3转基因（mCAV-3Tg）小鼠（肌营养不良症的动物模型）的咬肌中。将乱序（scr）-siRNA/ATCOL复合物注射到对侧肌肉中作为对照。注射后两周，咬肌解剖组织学分析。为了研究通过局部施用Mst-siRNA/ATCOL复合物的咬肌活动的变化，在整个实验期间通过遥测测量小鼠咬肌肌电图（EMG）。局部应用Mst-siRNA/ATCOL复合物后，咬肌增大，而在对侧没有观察到显著变化。组织学分析显示，Mst-siRNA/ATCOL复合物处理的咬肌肌原纤维明显大于对照侧。实时荧光定量PCR分析显示，Mst的表达显着下调mCAV-3Tg小鼠的治疗咬肌。此外，在Mst-siRNA处理的咬肌中，成肌转录因子的表达上调，而成脂转录因子的表达显著下调。EMG结果表明，通过局部施用Mst-siRNA/ATCOL复合物，mCAV-3Tg小鼠中的咬肌活动增加。这些数据表明，局部施用Mst-siRNA/ATCOL复合物可导致mCAV-3Tg小鼠的骨骼肌肥大和运动残疾的恢复。因此，ATCOL介导的siRNA应用是用于肌萎缩疾病的治疗用途的潜在工具。
Growing evidence suggests that small-interfering RNA (siRNA) can promote gene silencing in mammalian cells without induction of interferon synthesis or nonspecific gene suppression. Recently, a number of highly specific siRNAs targeted against disease-causing or disease-promoting genes have been developed. In this study, we evaluate the effectiveness of atelocollagen (ATCOL)-mediated application of siRNA targeting myostatin (Mst), a negative regulator of skeletal muscle growth, into skeletal muscles of muscular dystrophy model mice. We injected a nanoparticle complex containing myostatin-siRNA and ATCOL (Mst-siRNA/ATCOL) into the masseter muscles of mutant caveolin-3 transgenic (mCAV-3Tg) mice, an animal model for muscular dystrophy. Scrambled (scr) -siRNA/ATCOL complex was injected into the contralateral muscles as a control. Two weeks after injection, the masseter muscles were dissected for histometric analyses. To investigate changes in masseter muscle activity by local administration of Mst-siRNA/ATCOL complex, mouse masseter electromyography (EMG) was measured throughout the experimental period via telemetry. After local application of the Mst-siRNA/ATCOL complex, masseter muscles were enlarged, while no significant change was observed on the contralateral side. Histological analysis showed that myofibrils of masseter muscles treated with the Mst-siRNA/ATCOL complex were significantly larger than those of the control side. Real-time PCR analysis revealed a significant downregulation of Mst expression in the treated masseters of mCAV-3Tg mice. In addition, expression of myogenic transcription factors was upregulated in the Mst-siRNA-treated masseter muscle, while expression of adipogenic transcription factors was significantly downregulated. EMG results indicate that masseter muscle activity in mCAV-3Tg mice was increased by local administration of the Mst-siRNA/ATCOL complex. These data suggest local administration of Mst-siRNA/ATCOL complex could lead to skeletal muscle hypertrophy and recovery of motor disability in mCAV-3Tg mice. Therefore, ATCOL-mediated application of siRNA is a potential tool for therapeutic use in muscular atrophy diseases.
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影响因子：
5.5
作者：
Bottinelli, R;Canepari, M;Reggiani, C
通讯作者：
Reggiani, C
影响因子：
1.9
作者：
Kawai, Nobuhiko;Tanaka, Eiji;Tanne, Kazuo
通讯作者：
Tanne, Kazuo
影响因子：
3
作者：
Langenbach, GEJ;van Ruijven, LJ;van Eijden, TMGJ
通讯作者：
van Eijden, TMGJ
影响因子：
10.5
作者：
Rosen, ED;Hsu, CH;Spiegelman, BM
通讯作者：
Spiegelman, BM
影响因子：
3.5
作者：
Magee, Thomas R.;Artaza, Jorge N.;Gonzalez-Cadavid, Nestor F.
通讯作者：
Gonzalez-Cadavid, Nestor F.