Musculoskeletal Development and Regeneration Group, Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany.
Development and Disease Group, Max Planck Institute for Molecular Genetics, Berlin, Germany.
J Cachexia Sarcopenia Muscle. 2020 Dec;11(6):1758-1778. doi: 10.1002/jcsm.12632. Epub 2020 Oct 19.
Neurofibromatosis type 1 (NF1) is a multi-organ disease caused by mutations in neurofibromin 1 (NF1). Amongst other features, NF1 patients frequently show reduced muscle mass and strength, impairing patients' mobility and increasing the risk of fall. The role of Nf1 in muscle and the cause for the NF1-associated myopathy are mostly unknown.
To dissect the function of Nf1 in muscle, we created muscle-specific knockout mouse models for NF1, inactivating Nf1 in the prenatal myogenic lineage either under the Lbx1 promoter or under the Myf5 promoter. Mice were analysed during prenatal and postnatal myogenesis and muscle growth.
Nf1 and Nf1 animals showed only mild defects in prenatal myogenesis. Nf1 animals were perinatally lethal, while Nf1 animals survived only up to approximately 25 weeks. A comprehensive phenotypic characterization of Nf1 animals showed decreased postnatal growth, reduced muscle size, and fast fibre atrophy. Proteome and transcriptome analyses of muscle tissue indicated decreased protein synthesis and increased proteasomal degradation, and decreased glycolytic and increased oxidative activity in muscle tissue. High-resolution respirometry confirmed enhanced oxidative metabolism in Nf1 muscles, which was concomitant to a fibre type shift from type 2B to type 2A and type 1. Moreover, Nf1 muscles showed hallmarks of decreased activation of mTORC1 and increased expression of atrogenes. Remarkably, loss of Nf1 promoted a robust activation of AMPK with a gene expression profile indicative of increased fatty acid catabolism. Additionally, we observed a strong induction of genes encoding catabolic cytokines in muscle Nf1 animals, in line with a drastic reduction of white, but not brown adipose tissue.
Our results demonstrate a cell autonomous role for Nf1 in myogenic cells during postnatal muscle growth required for metabolic and proteostatic homeostasis. Furthermore, Nf1 deficiency in muscle drives cross-tissue communication and mobilization of lipid reserves.
神经纤维瘤病 1 型（NF1）是一种多器官疾病，由神经纤维瘤蛋白 1（NF1）突变引起。除其他特征外，NF1 患者常表现出肌肉质量和力量下降，这会影响患者的活动能力并增加跌倒的风险。Nf1 在肌肉中的作用以及 NF1 相关肌病的原因在很大程度上尚不清楚。
为了剖析 Nf1 在肌肉中的功能，我们创建了肌肉特异性 NF1 敲除小鼠模型，使用 Lbx1 启动子或 Myf5 启动子在产前肌源性谱系中使 Nf1 失活。在产前和产后肌发生和肌肉生长过程中对小鼠进行分析。
Nf1 和 Nf1 动物仅在产前肌发生中表现出轻度缺陷。Nf1 动物在围产期致死，而 Nf1 动物仅存活至大约 25 周。对 Nf1 动物的全面表型特征分析表明，出生后生长缓慢，肌肉体积减小，快速纤维萎缩。肌肉组织的蛋白质组和转录组分析表明蛋白质合成减少，蛋白酶体降解增加，肌肉组织的糖酵解减少，氧化活性增加。高分辨率呼吸测定法证实 Nf1 肌肉中的氧化代谢增强，同时伴有纤维类型从 2B 型向 2A 型和 1 型的转变。此外，Nf1 肌肉表现出 mTORC1 活性降低和自噬基因表达增加的特征。值得注意的是，Nf1 的缺失促进了 AMPK 的强烈激活，其基因表达谱表明脂肪酸分解代谢增加。此外，我们在肌肉 Nf1 动物中观察到编码代谢性细胞因子的基因强烈诱导，与白色脂肪组织但不是棕色脂肪组织的急剧减少一致。
我们的结果表明，Nf1 在肌肉中的细胞自主性作用对于出生后肌肉生长的代谢和蛋白质稳态是必需的。此外，肌肉中 Nf1 的缺乏会驱动跨组织通讯和动员脂质储备。
