Enhanced pro-BDNF-p75NTR pathway activity in denervated skeletal muscle.-猫眼课题宝

DOI：

10.1016/j.lfs.2021.120067

发表时间：

2021-12-01

期刊：

Life sciences

影响因子：

6.1

通讯作者：

中科院分区：

医学2区

文献类型：

作者：

Aby K;Antony R;Eichholz M;Srinivasan R;Li Y

来源链接：

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8595791/

脑源性神经营养因子（BDNF）及其相关受体TrkB和p75 NTR在骨骼肌中表达，但其功能仍有待充分了解。骨骼肌去神经支配，发生在脊髓损伤，周围神经病变和衰老，对肌肉质量和功能产生负面影响。在这项研究中，我们希望了解BDNF，TrkB和p75NTR在骨骼肌失神经诱导的不良反应中的作用。使用单侧坐骨神经切除的小鼠。蛋白质水平的前和成熟的BDNF，TrkB，p75 NTR，其下游信号通路的激活，并在控制和失神经肌肉炎症进行了测定与Western印迹和组织染色。用p75NTR抑制剂和BDNF骨骼肌特异性敲除小鼠进行治疗，以检查p75NTR和pro-BDNF的作用。在失神经肌肉中，pro-BDNF和p75 NTR显著上调，p75 NTR的两条主要下游信号通路JNK和NF-kB被激活，沿着肌肉萎缩和炎症。使用LM11A-31抑制p75NTR显著降低了失神经肌肉中的JNK活化和炎性细胞因子。此外，骨骼肌特异性敲除BDNF可降低去神经肌肉中的pro-BDNF水平、JNK激活和炎症。这些结果首次揭示了pro-BDNF的上调和p75NTR通路的激活参与了去神经诱导的骨骼肌炎症反应。提示抑制pro-BDNF-p75NTR通路可能成为治疗骨骼肌炎症的新靶点。

Brain derived neurotrophic factor (BDNF) and the related receptors TrkB and p75NTR are expressed in skeletal muscle, yet their functions remain to be fully understood. Skeletal muscle denervation, which occurs in spinal injury, peripheral neuropathies, and aging, negatively affects muscle mass and function. In this study, we wanted to understand the role of BDNF, TrkB, and p75NTR in denervation-induced adverse effects on skeletal muscle. Mice with unilateral sciatic denervation were used. Protein levels of pro- and mature BDNF, TrkB, p75NTR, activations of their downstream signaling pathways, and inflammation in the control and denervated muscle were measured with Western blot and tissue staining. Treatment with a p75NTR inhibitor and BDNF skeletal muscle specific knockout in mice were used to examine the role of p75NTR and pro-BDNF. In denervated muscle, pro-BDNF and p75NTR were significantly upregulated, and JNK and NF-kB, two major downstream signaling pathways of p75NTR, were activated, along with muscle atrophy and inflammation. Inhibition of p75NTR using LM11A-31 significantly reduced JNK activation and inflammatory cytokines in the denervated muscle. Moreover, skeletal muscle specific knockout of BDNF reduced pro-BDNF level, JNK activation and inflammation in the denervated muscle. These results reveal for the first time that the upregulation of pro-BDNF and activation of p75NTR pathway are involved in denervation-induced inflammation in skeletal muscle. The results suggest that inhibition of pro-BDNF-p75NTR pathway can be a new target to treat skeletal muscle inflammation.