Injection of FGF6 accelerates regeneration of the soleus muscle in adult mice (original) (raw)
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IGF-II is up-regulated and myofibres are hypertrophied in regenerating soleus of mice lacking FGF6
Experimental Cell Research, 2004
Important functions in myogenesis have been proposed for FGF6, a member of the fibroblast growth factor family accumulating almost exclusively in the myogenic lineage. However, the use of FGF6(À/À) mutant mice gave contradictory results and the role of FGF6 during myogenesis remains largely unclear. Using FGF6(À/À) mice, we first analysed the morphology of the regenerated soleus following cardiotoxin injection and showed hypertrophied myofibres in soleus of the mutant mice as compared to wild-type mice. Secondly, to examine the function of the IGF family in the hypertrophy process, we used semiquantitative and real-time RT-PCR assays and Western blots to monitor the expression of the insulin-like growth factors (IGF-I and IGF-II), their receptors [type I IGF receptor (IGF1R) and IGF-II receptor (IGF2R)], and of a binding protein IGFBP-5 in regenerating soleus muscles of FGF6(À/À) knockout mice vs. wild-type mice. In the mutant, both IGF-II and IGF2R, but not IGF-I and IGF1R, were strongly up-regulated, whereas IGFBP5 was down-regulated, strongly suggesting that, in the absence of FGF6, the mechanisms leading to myofibre hypertrophy were mediated specifically by an IGF-II/IGF2R signalling pathway distinct from the classic mechanism involving IGF-I and IGF1R previously described for skeletal muscle hypertrophy. The potential regulating role of IGFBP5 on IGF-II expression is also discussed. This report shows for the first time a specific role for FGF6 in the regulation of myofibre size during a process of in vivo myogenesis. D
Biochimica Et Biophysica Acta-molecular Cell Research, 2006
Important functions in myogenesis have been proposed for FGF6, a member of the fibroblast growth factor family accumulating almost exclusively in the myogenic lineage. However, the analyses of Fgf6 (−/−) mutant mice gave contradictory results and the role of FGF6 during myogenesis remained largely unclear. Recent reports support the concept that FGF6 has a dual function in muscle regeneration, stimulating myoblast proliferation/migration and muscle differentiation/hypertrophy in a dose-dependent manner. The alternative use of distinct signaling pathways recruiting either FGFR1 or FGFR4 might explain the dual role of FGF6 in myogenesis. A role for FGF6 in the maintenance of a reserve pool of progenitor cells in the skeletal muscle has been also strongly suggested. The aim of this review is to summarize our knowledge on the involvement of FGF6 in myogenesis.
Delayed angiogenesis and VEGF production in CCR2 / mice during impaired skeletal muscle regeneration
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2007
The regulation of vascular endothelial growth factor (VEGF) levels and angiogenic events during skeletal muscle regeneration remains largely unknown. This study examined angiogenesis, VEGF levels, and muscle regeneration after cardiotoxin (CT)-induced injury in mice lacking the CC chemokine receptor 2 (CCR2). Muscle regeneration was significantly decreased in CCR2 -/-mice as was the early accumulation of macrophages after injury. In both mouse strains, tissue VEGF was similar at baseline (no injections) and significantly decreased at day 3 post-CT. Tissue VEGF in WT mice was restored within 7 days post-injury but remained significantly reduced in CCR2 -/mice until day 21. Capillary density (capillaries/mm 2 ) within regenerating muscle was maximal in WT mice at day 7 and double that of baseline muscle. In comparison, maximal capillary density in CCR2 -/-mice occurred at 21 days post-injury. Maximal capillary density developed concurrent with the restoration of tissue VEGF in both strains. A highly significant, inverse relationship existed between the size of regenerated muscle fibers and capillaries/mm 2 . While this relationship was comparable in WT and CCR2 -/-animals, there was a significant decrease in the magnitude of this response in the absence of CCR2, reflecting the observation that regenerated muscle fiber size in CCR2 -/-mice was only 50% of baseline at 42 days post-injury while WT mice had attained baseline fiber size by day 21. Thus, CCR2-dependent events in injured skeletal muscle, including impaired macrophage recruitment, contribute to restoration of tissue VEGF levels and the dynamic processes of capillary formation and muscle regeneration.
International Congress Series, 2007
One of the most exciting aspirations of current medical science is the regeneration of damaged body parts. The capacity of adult tissues to regenerate in response to injury stimuli represents an important homeostatic process that until recently was thought to be limited in mammals to tissues with high turnover such as blood and skin. However, this central dogma of cell biology has been revised on the basis of recent experimental evidence that even the adult brain is able to undergo repair. It is now generally accepted that each tissue type, even those such as nerves or muscle that are considered postmitotic, contains a reserve of undifferentiated progenitor cells, loosely termed stem cells, that participate in tissue regeneration and repair. Regeneration represents a coordinate process in which these stem cell populations are activated to maintain and preserve tissue structure and function upon injured stimuli. In this review we will discuss the molecular and cellular basis of muscle regeneration, the critical role of IGF-1 on muscle homeostasis, and its potential therapeutic approach to improve muscle regeneration and to attenuate atrophy and frailty associated with muscle diseases.
Vascular Endothelial Growth Factor Stimulates Skeletal Muscle Regeneration In Vivo
Molecular Therapy, 2004
Vascular endothelial growth factor (VEGF) is a major regulator of blood vessel formation during development and in the adult organism. Recent evidence indicates that this factor also plays an important role in sustaining the proliferation and differentiation of different cell types, including progenitor cells of different tissues, including bone marrow, bone, and the central nervous system. Here we show that the delivery of the 165-aa isoform of VEGF-A cDNA using an adeno-associated virus (AAV) vector exerts a powerful effect on skeletal muscle regeneration in vivo. Following ischemia-, glycerol-, or cardiotoxin-induced damage in mouse skeletal muscle, the delivery of AAV-VEGF markedly improved muscle fiber reconstitution with a dose-dependent effect. The expression of both VEGF receptor-1 (VEGFR-1) and VEGFR-2 was upregulated both in the satellite cells of the damaged muscles and during myotube formation in vitro; the VEGF effect was mediated by the VEGFR-2, since the transfer of PlGF, a VEGF family member interacting with the VEGFR-1, was ineffective. These results are consistent with the observation that VEGF promotes the growth of myogenic fibers and protects the myogenic cells from apoptosis in vitro and prompt a therapeutic use for VEGF gene transfer in a variety of muscular disorders.
Growth factors improve muscle healing in vivo
The Journal of Bone and Joint Surgery, 2000
I njury to muscles is very common. We have previously observed that basic fibroblast growth factor (b-FGF), insulin growth factor type 1 (IGF-1) and nerve growth factor (NGF) are potent stimulators of the proliferation and fusion of myoblasts in vitro. We therefore injected these growth factors into mice with lacerations of the gastrocnemius muscle. The muscle regeneration was evaluated at one week by histological staining and quantitative histology. Muscle healing was assessed histologically and the contractile properties were measured one month after injury.