Reduced Mobility of Fibroblast Growth Factor (FGF)-Deficient Myoblasts Might Contribute to Dystrophic Changes in the Musculature of FGF2/FGF6/mdx Triple-Mutant Mice

Abstract

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.