Cassano Marco, Biressi Stefano, Finan Amanda, Benedetti Laura, Omes Claudia, Boratto Renata, Martin Frank, Allegretti Marcello, Broccoli Vania, Cusella De Angelis Gabriella, Comoglio Paolo M, Basilico Cristina, Torrente Yvan, Michieli Paolo, Cossu Giulio, Sampaolesi Maurilio
Translational Cardiomyology, Stem Cell Institute Leuven, KULeuven, Leuven, Belgium.
PLoS One. 2008 Sep 16;3(9):e3223. doi: 10.1371/journal.pone.0003223.
Hepatocyte Growth Factor (HGF) is a pleiotropic cytokine of mesenchymal origin that mediates a characteristic array of biological activities including cell proliferation, survival, motility and morphogenesis. Its high affinity receptor, the tyrosine kinase Met, is expressed by a wide range of tissues and can be activated by either paracrine or autocrine stimulation. Adult myogenic precursor cells, the so called satellite cells, express both HGF and Met. Following muscle injury, autocrine HGF-Met stimulation plays a key role in promoting activation and early division of satellite cells, but is shut off in a second phase to allow myogenic differentiation. In culture, HGF stimulation promotes proliferation of muscle precursors thereby inhibiting their differentiation.
METHODOLOGY/PRINCIPAL FINDINGS: Magic-Factor 1 (Met-Activating Genetically Improved Chimeric Factor-1 or Magic-F1) is an HGF-derived, engineered protein that contains two Met-binding domains repeated in tandem. It has a reduced affinity for Met and, in contrast to HGF it elicits activation of the AKT but not the ERK signaling pathway. As a result, Magic-F1 is not mitogenic but conserves the ability to promote cell survival. Here we show that Magic-F1 protects myogenic precursors against apoptosis, thus increasing their fusion ability and enhancing muscular differentiation. Electrotransfer of Magic-F1 gene into adult mice promoted muscular hypertrophy and decreased myocyte apoptosis. Magic-F1 transgenic mice displayed constitutive muscular hypertrophy, improved running performance and accelerated muscle regeneration following injury. Crossing of Magic-F1 transgenic mice with alpha-sarcoglycan knock-out mice -a mouse model of muscular dystrophy- or adenovirus-mediated Magic-F1 gene delivery resulted in amelioration of the dystrophic phenotype as measured by both anatomical/histological analysis and functional tests.
CONCLUSIONS/SIGNIFICANCE: Because of these features Magic-F1 represents a novel molecular tool to counteract muscle wasting in major muscular diseases such as cachexia or muscular dystrophy.
肝细胞生长因子（HGF）是一种间充质来源的多效性细胞因子，介导一系列特征性的生物学活性，包括细胞增殖、存活、迁移和形态发生。其高亲和力受体——酪氨酸激酶Met，在多种组织中表达，可通过旁分泌或自分泌刺激而激活。成年肌源性前体细胞，即所谓的卫星细胞，同时表达HGF和Met。肌肉损伤后，自分泌的HGF-Met刺激在促进卫星细胞的激活和早期分裂中起关键作用，但在第二阶段会关闭，以允许肌源性分化。在培养中，HGF刺激促进肌肉前体细胞的增殖，从而抑制其分化。
方法/主要发现：神奇因子1（Met激活基因改良嵌合因子-1或神奇F1）是一种源自HGF的工程蛋白，包含两个串联重复的Met结合结构域。它与Met的亲和力降低，与HGF不同的是，它能激活AKT信号通路，但不能激活ERK信号通路。因此，神奇F1没有促有丝分裂作用，但保留了促进细胞存活的能力。在这里，我们表明神奇F1可保护肌源性前体细胞免于凋亡，从而提高其融合能力并增强肌肉分化。将神奇F1基因电转移到成年小鼠体内可促进肌肉肥大并减少肌细胞凋亡。神奇F1转基因小鼠表现出持续性肌肉肥大、跑步性能改善以及损伤后肌肉再生加速。将神奇F1转基因小鼠与α-肌聚糖敲除小鼠（一种肌肉营养不良的小鼠模型）杂交，或通过腺病毒介导的神奇F1基因递送，通过解剖学/组织学分析和功能测试均发现，营养不良表型得到改善。
结论/意义：由于这些特性，神奇F1代表了一种新型分子工具，可对抗诸如恶病质或肌肉营养不良等主要肌肉疾病中的肌肉萎缩。
