Neuhaus Petra, Oustanina Svetlana, Loch Tomasz, Krüger Marcus, Bober Eva, Dono Rosanna, Zeller Rolf, Braun Thomas
Institute of Physiological Chemistry, University of Halle-Wittenberg, 06097 Halle, Germany.
Mol Cell Biol. 2003 Sep;23(17):6037-48. doi: 10.1128/MCB.23.17.6037-6048.2003.
Development and regeneration of muscle tissue is a highly organized, multistep process that requires cell proliferation, migration, differentiation, and maturation. Previous data implicate fibroblast growth factors (FGFs) as critical regulators of these processes, although their precise role in vivo is still not clear. We have explored the consequences of the loss of multiple FGFs (FGF2 and FGF6 in particular) for muscle regeneration in mdx mice, which serve as a model for chronic muscle damage. We show that the combined loss of FGF2 and FGF6 leads to severe dystrophic changes in the musculature. We found that FGF6 mutant myoblasts had decreased migration ability in vivo, whereas wild-type myoblasts migrated normally in a FGF6 mutant environment after transplantation of genetically labeled myoblasts from FGF6 mutants in wild-type mice and vice versa. In addition, retrovirus-mediated expression of dominant-negative versions of Ras and Ral led to a reduced migration of transplanted myoblasts in vivo. We propose that FGFs are critical components of the muscle regeneration machinery that enhance skeletal muscle regeneration, probably by stimulation of muscle stem cell migration.
肌肉组织的发育和再生是一个高度有序的多步骤过程，需要细胞增殖、迁移、分化和成熟。先前的数据表明成纤维细胞生长因子（FGFs）是这些过程的关键调节因子，尽管它们在体内的确切作用仍不清楚。我们探讨了多种FGFs（特别是FGF2和FGF6）缺失对mdx小鼠肌肉再生的影响，mdx小鼠可作为慢性肌肉损伤的模型。我们发现FGF2和FGF6的联合缺失会导致肌肉组织出现严重的营养不良性变化。我们发现，FGF6突变体成肌细胞在体内的迁移能力下降，而在将FGF6突变体的基因标记成肌细胞移植到野生型小鼠体内后，野生型成肌细胞在FGF6突变体环境中能正常迁移，反之亦然。此外，逆转录病毒介导的Ras和Ral显性负性变体的表达导致移植的成肌细胞在体内的迁移减少。我们认为，FGFs是肌肉再生机制的关键组成部分，可能通过刺激肌肉干细胞迁移来促进骨骼肌再生。
