Orthopaedic Research & Biotechnology, The Children's Hospital at Westmead, Westmead, NSW, Australia; Discipline of Paediatrics & Child Heath, Faculty of Medicine, University of Sydney, Camperdown, NSW, Australia.
Orthopaedic Research & Biotechnology, The Children's Hospital at Westmead, Westmead, NSW, Australia.
Mol Genet Metab. 2018 Apr;123(4):518-525. doi: 10.1016/j.ymgme.2018.02.009. Epub 2018 Feb 16.
Neurofibromatosis Type 1 (NF1) is a common autosomal dominant genetic disorder While NF1 is primarily associated with predisposition for tumor formation, muscle weakness has emerged as having a significant impact on quality of life. NF1 inactivation is linked with a canonical upregulation Ras-MEK-ERK signaling. This in this study we tested the capacity of the small molecule MEK inhibitor PD0325901 to influence the intramyocellular lipid accumulation associated with NF1 deficiency. Established murine models of tissue specific Nf1 deletion in skeletal muscle (Nf1) and limb mesenchyme (Nf1) were tested. Developmental PD0325901 dosing of dams pregnant with Nf1 progeny rescued the phenotype of day 3 pups including body weight and lipid accumulation by Oil Red O staining. In contrast, PD0325901 treatment of 4 week old Nf1 mice for 8 weeks had no impact on body weight, muscle wet weight, activity, or intramyocellular lipid. Examination of day 3 Nf1 pups showed differences between the two tissue-specific knockout strains, with lipid staining greatest in Nf1 mice, and fibrosis higher in Nf1 mice. These data show that a MEK/ERK dependent mechanism underlies NF1 muscle metabolism during development. However, crosstalk from Nf1-deficient non-muscle mesenchymal cells may impact upon muscle metabolism and fibrosis in neonatal and mature myofibers.
神经纤维瘤病 1 型（NF1）是一种常见的常染色体显性遗传疾病。虽然 NF1 主要与肿瘤形成易感性有关，但肌肉无力已成为影响生活质量的重要因素。NF1 的失活与 Ras-MEK-ERK 信号的经典上调有关。在本研究中，我们测试了小分子 MEK 抑制剂 PD0325901 影响与 NF1 缺乏相关的肌内脂质积累的能力。测试了骨骼肌（Nf1）和肢体间充质（Nf1）组织特异性 Nf1 缺失的小鼠模型。对携带 Nf1 后代的孕鼠进行 PD0325901 的发育剂量给药，挽救了第 3 天幼鼠的表型，包括体重和油红 O 染色的脂质积累。相比之下，PD0325901 治疗 4 周龄 Nf1 小鼠 8 周对体重、肌肉湿重、活动或肌内脂质没有影响。对第 3 天 Nf1 幼鼠的检查显示两种组织特异性敲除株之间存在差异，Nf1 小鼠的脂质染色最强，Nf1 小鼠的纤维化程度更高。这些数据表明，MEK/ERK 依赖性机制是 NF1 肌肉代谢在发育过程中的基础。然而，来自 NF1 缺陷的非肌肉间充质细胞的串扰可能会影响新生儿和成熟肌纤维的肌肉代谢和纤维化。
