Neurotrophin 4/5 is required for the normal development of the slow muscle fiber phenotype in the rat soleus.
During normal postnatal development, rat soleus (SOL) muscle fibers undergo a dramatic fast-to-slow myosin heavy chain (MyHC) isoform transformation. We exploited this phenomenon to evaluate the role of neurotrophin 4/5 (NT-4/5) in the regulation of muscle fiber phenotype. Intramuscular injections of recombinant NT-4/5 into the SOL muscle of rat neonates significantly accelerated the normal fast-to-slow MyHC isoform transformation. Sequestration of endogenous NT-4/5 with TrkB-IgG prevented this transformation from occurring. Administration of the other TrkB ligand, brain-derived neurotrophic factor (BDNF), did not affect the normal course of the MyHC isoform transformation in this muscle, indicating that the observed effect is NT-4/5 specific. Botulinum toxin blockade of synaptic transmission significantly disrupted the normal fast-to-slow MyHC isoform switch. Because administration of NT-4/5 to paralyzed muscles failed to restore the normal course of this MyHC transformation, we believe that the effect of NT-4/5 is not directly on the muscle fibers but that it probably activates or forms a type of retrograde signal to motoneurons. The developmental upregulation of NT-4/5 mRNA in rat SOL muscle fibers occurred earlier than the upregulation of MyHC I/b mRNA associated with muscle fiber transformation. This timing is consistent with the idea that NT-4/5 is involved in early events that lead to the upregulation of the slow MyHC isoform in this muscle.
Carrasco
Dario I
DI
Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA. dcarras@emory.edu
English
Arthur W
AW
D000818:Animals; D001905:Botulinum Toxins / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D017931:DNA Primers; D007150:Immunohistochemistry; D008954:Models, Biological; D018657:Muscle Fibers, Slow-Twitch / Q000502:physiology*; D018482:Muscle, Skeletal / Q000254:growth & development*; D018995:Myosin Heavy Chains / Q000502:physiology; D009414:Nerve Growth Factors / Q000502:physiology*; D019148:Neuromuscular Blockade; D020033:Protein Isoforms / Q000187:drug effects / Q000502:physiology; D051381:Rats / Q000254:growth & development* / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
D019208:Brain-Derived Neurotrophic Factor; D017931:DNA Primers; D009414:Nerve Growth Factors; D020033:Protein Isoforms; C071951:neurotrophin 5; D001905:Botulinum Toxins; D018995:Myosin Heavy Chains; C073922:neurotrophin 4