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Journal of Neuroscience, Vol 14, 3378-3388, Copyright © 1994 by Society for Neuroscience
Signaling by insulin-like growth factors in paralyzed skeletal muscle: rapid induction of IGF1 expression in muscle fibers and prevention of interstitial cell proliferation by IGF-BP5 and IGF-BP4
P Caroni and C Schneider
Friedrich Miescher Institute, Basel, Switzerland.
In the absence of muscle activity, muscle fibers, muscle interstitial
cells, and intramuscular nerves display characteristic reactions presumably
aimed at restoring a functioning neuromuscular system and avoiding
degenerative events. In partially denervated muscle these include
proliferation of interstitial cells, followed by nerve sprouting. The same
reactions can be induced in intact muscle by elevation of intramuscular
insulin-like growth factor (IGF) levels. To determine whether IGFs may
participate in the initiation of restorative reactions in inactivated
muscle we analyzed the expression of IGF1 and IGF2 mRNA in botulinum
toxin-paralyzed and in denervated rat skeletal muscle, and interfered with
the activity of IGFs by locally applying the IGF-binding proteins IGF-BP5
and IGF-BP4. To obtain a resolution of the in situ hybridization signals at
the cellular level, a nonradioactive method based on digoxigenin-labeled
probes was applied. We found that muscle fiber IGF1 mRNA increased rapidly
and transiently in inactivated muscle. The time course of this response was
similar to that reported for ACh receptor subunits and myogenins. A similar
behavior was observed for the corresponding IGF1 protein. The IGF1 response
coincided with the transient muscle interstitial cell proliferation
reaction. Local application of recombinant IGF-BP5 or IGF- BP4, which are
endogenous and specific extracellular ligands of IGFs, prevented the
stimulation of interstitial cell proliferation in paralyzed muscle. Our
data demonstrate the elevated production of the growth factor IGF1 among
early reactions in electrically inactive skeletal muscle fibers and
indicate that muscle IGFs are required for the induction of intramuscular
interstitial cell proliferation. These findings support the hypothesis that
in the neuromuscular system IGF1 plays an important role in initiating
cellular reactions in the vicinity of inactive muscle fibers.
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