Role of muscle insulin-like growth factors in nerve sprouting: suppression of terminal sprouting in paralyzed muscle by IGF-binding protein 4.
Role of muscle insulin-like growth factors in nerve sprouting: suppression of terminal sprouting in paralyzed muscle by IGF-binding protein 4.
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DOI：
10.1083/jcb.125.4.893
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发表时间：
1994-05
期刊：
影响因子：
--
通讯作者：
Zapf J
中科院分区：
文献类型：
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作者：
Caroni P;Schneider C;Kiefer MC;Zapf J
肌肉激活的长期缺乏引发复杂的细胞和分子反应，旨在恢复功能性神经肌肉传递和预防退行性过程。这些反应的一个中心方面是在失活的肌纤维附近肌内神经的发芽。从末端神经分支和Ranvier节点出现的芽可以与失活的肌纤维重新建立功能性接触，这是神经肌肉系统病理条件下的重要恢复过程。由于它们在非活性骨骼肌纤维中的快速上调和它们在成人肌肉中诱导神经发芽的能力，胰岛素样生长因子（IGF）是促进神经肌肉系统中的恢复反应的候选信号分子。在这项研究中，我们利用了高亲和力和特异性的IGF结合蛋白4（IGF-BP 4）和IGF-BP 5的IGF 1和IGF 2，以确定这些生长因子是否参与瘫痪骨骼肌的神经发芽反应。在感觉和运动神经元的组织培养实验中，我们证明了IGF 1的轴突促进活性被IGF-BP 4阻断，并且在瘫痪的肌肉提取物中检测到类似的IGF-BP敏感活性，但不从控制肌肉中检测到。在体内实验中，我们表明，局部递送IGF-BP 4到肉毒毒素A麻痹的骨骼肌有效地防止了肌肉中的神经发芽。我们的研究结果表明肌肉IGF在肌内神经发芽中发挥着重要作用。此外，这些发现表明IGFs是来自失活肌肉的主要信号因子，以促进局部恢复反应，包括间质细胞增殖和神经发芽。
The protracted absence of muscle activation initiates complex cellular and molecular reactions aimed at restoring functional neuromuscular transmission and preventing degenerative processes. A central aspect of these reactions is the sprouting of intramuscular nerves in the vicinity of inactivated muscle fibers. Sprouts emerging from terminal nerve branches and nodes of Ranvier can reestablish functional contacts with inactive muscle fibers, and this is an essential restorative process in pathological conditions of the neuromuscular system. Due to their rapid upregulation in inactive skeletal muscle fibers and their ability to induce nerve sprouting in adult muscle, insulin-like growth factors (IGFs) are candidate signaling molecules to promote restorative reactions in the neuromuscular system. In this study we have exploited the high affinity and specificity of IGF-binding protein 4 (IGF-BP4) and IGF-BP5 for IGF1 and IGF2 to determine whether these growth factors are involved in the nerve sprouting reaction in paralyzed skeletal muscle. In tissue culture experiments with sensory- and motoneurons we demonstrate that the neurite promoting activity of IGF1 is blocked by IGF-BP4, and that a similar IGF-BP-sensitive activity is detected in muscle extracts from paralyzed, but not from control muscle. In in vivo experiments, we show that local delivery of IGF-BP4 to Botulinum toxin A-paralyzed skeletal muscle effectively prevents nerve sprouting in that muscle. Our findings indicate that muscle IGFs play an essential role in intramuscular nerve sprouting. In addition, these findings suggest that IGFs are major signaling factors from inactivated muscle to promote local restorative reactions, including interstitial cell proliferation and nerve sprouting.