The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
Department of Neurosurgery, Henry Ford Hospital, Detroit, MI, USA.
Cell Death Dis. 2019 Jan 28;10(2):82. doi: 10.1038/s41419-019-1307-9.
Duchenne muscular dystrophy (DMD) is a progressive, lethal, X-linked disease of skeletal and cardiac muscles caused by mutations in the dystrophin gene. Loss of dystrophin leads to muscle fiber damage and impairment of satellite cell asymmetric division, which are essential for muscle regeneration. These processes ultimately result in muscle wasting and the replacement of the degenerating muscles by fibrogenic cells, a process that leads to the generation of fibrotic tissues. Preimplantation factor (PIF) is an evolutionary conserved 15-amino acid peptide secreted by viable mammalian embryos. Synthetic PIF (sPIF) reproduces the protective/regenerative effects of the endogenous peptide in immune disorders and transplantation models. In this study, we demonstrated that sPIF treatment promoted mouse and human myoblast differentiation and inhibited the expression of collagen 1A1, collagen 1A2, and TGF-β in DMD patient-derived myoblasts. Additionally, sPIF increased the expression of utrophin, a homolog of dystrophin protein. sPIF effects were mediated via the upregulation of lncRNA H19 and miR-675 and downregulation of let-7. sPIF also inhibited the expression of miR-21, a major fibrosis regulator. The administration of sPIF in mdx mice significantly decreased serum creatine kinase and collagen I and collagen IV expression in the diaphragm, whereas it increased utrophin expression in the diaphragm, heart and quadriceps muscles. In conclusion, sPIF promoted the differentiation of DMD myoblasts, increased utrophin expression via the H19/miRNA-675/let-7 pathway, and reduced muscle fibrosis possibly via the upregulation of miR-675 and inhibition of miR-21 expression. These findings strongly support pursuing sPIF as a potential therapeutic agent for DMD. Moreover, the completion of an sPIF phase I safety trial will further promote the use of sPIF for the treatment of muscular dystrophies.
杜氏肌营养不良症（DMD）是一种进行性、致命的 X 连锁骨骼肌和心肌疾病，由肌营养不良蛋白基因的突变引起。肌营养不良蛋白的缺失导致肌肉纤维损伤和卫星细胞不对称分裂受损，这对肌肉再生至关重要。这些过程最终导致肌肉萎缩，退化的肌肉被纤维原细胞取代，这一过程导致纤维化组织的产生。着床前因子（PIF）是一种进化上保守的 15 个氨基酸肽，由有活力的哺乳动物胚胎分泌。合成 PIF（sPIF）在免疫紊乱和移植模型中复制内源性肽的保护/再生作用。在这项研究中，我们证明了 sPIF 处理促进了小鼠和人成肌细胞的分化，并抑制了 DMD 患者来源的成肌细胞中胶原 1A1、胶原 1A2 和 TGF-β的表达。此外，sPIF 增加了肌营养不良蛋白蛋白同源物 utrophin 的表达。sPIF 的作用是通过上调 lncRNA H19 和 miR-675 以及下调 let-7 来介导的。sPIF 还抑制了 miR-21 的表达，miR-21 是一种主要的纤维化调节剂。在 mdx 小鼠中给予 sPIF 可显著降低血清肌酸激酶和膈肌胶原 I 和胶原 IV 的表达，同时增加膈肌、心脏和四头肌 utrophin 的表达。总之，sPIF 促进了 DMD 成肌细胞的分化，通过 H19/miRNA-675/let-7 途径增加 utrophin 的表达，并可能通过上调 miR-675 和抑制 miR-21 的表达减少肌肉纤维化。这些发现强烈支持将 sPIF 作为 DMD 的潜在治疗药物进行研究。此外，sPIF 一期安全性试验的完成将进一步促进 sPIF 用于治疗肌肉营养不良症。
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