Nicolino Silvia, Panetto Arianna, Raimondo Stefania, Gambarotta Giovanna, Guzzini Matteo, Fornaro Michele, Battiston Bruno, Tos Perluigi, Geuna Stefano, Perroteau Isabelle
Dipartimento di Biologia Animale e dell'Uomo, Università di Torino, Torino, Italy.
Microsurgery. 2009;29(6):464-72. doi: 10.1002/micr.20636.
Skeletal muscle atrophy represents one of the main causes of poor outcome of microsurgical nerve reconstruction. Recent studies have pointed to the importance of the neuregulin/ErbB signaling pathway in the development and regeneration of the neuromuscular system. Here, we show by immunohistochemistry, RT-PCR, and Western blotting analyses, in an in vivo model of adult skeletal muscle denervation/reinnervation, that expression of Neuregulin1 (NRG1) and ErbB receptors is regulated by the innervation condition. We found out that a significant upregulation of the alpha-, but not beta-, isoform of NRG1, as well as of ErbB2, ErbB3, and ErbB4-cyt1 isoform occurs as a consequence of denervation of flexor digitorum muscles of the rat forelimb by median nerve transection. Moreover, after tubulization median nerve repair, and consequent muscle reinnervation, all messengers of the NRG1/ErbB system are promptly downregulated. Therefore, our results suggest the existence of a alpha-NRG1-mediated autocrine and/or paracrine trophic loop in skeletal muscles that is activated after denervation and promptly deactivated after nerve reconstruction. This myotrophic loop is a promising therapeutic target for the prevention of muscle atrophy. Yet, the recent demonstration of a similar alpha-NRG1-mediated gliotrophic loop in denervated Schwann cells provides a possible explanation for the effectiveness of muscle conduits for tubulization nerve repair.
骨骼肌萎缩是显微外科神经重建效果不佳的主要原因之一。最近的研究指出了神经调节蛋白/表皮生长因子受体（ErbB）信号通路在神经肌肉系统发育和再生中的重要性。在此，我们通过免疫组织化学、逆转录-聚合酶链反应（RT-PCR）和蛋白质免疫印迹分析，在成年骨骼肌去神经/再神经支配的体内模型中表明，神经调节蛋白1（NRG1）和ErbB受体的表达受神经支配状态的调节。我们发现，由于正中神经横断导致大鼠前肢指浅屈肌去神经支配，NRG1的α-亚型（而非β-亚型）以及ErbB2、ErbB3和ErbB4-cyt1亚型均出现显著上调。此外，在进行套管法正中神经修复以及随后的肌肉再神经支配后，NRG1/ErbB系统的所有信使分子均迅速下调。因此，我们的结果表明，骨骼肌中存在一个由α-NRG1介导的自分泌和/或旁分泌营养回路，该回路在去神经支配后被激活，并在神经重建后迅速失活。这个肌营养回路是预防肌肉萎缩的一个有前景的治疗靶点。然而，最近在去神经支配的施万细胞中发现了类似的由α-NRG1介导的神经胶质营养回路，这为肌肉导管用于套管法神经修复的有效性提供了一种可能的解释。
