Approximately half of the fibers in rat soleus undergo a dramatic switch in myosin heavy chain (MyHC) isoform content from fast to slow during postnatal development. Neurotrophin 4/5 (NT-4/5) messenger RNA in skeletal muscle increases significantly during this period of life. Its production is modulated by neuromuscular activity. In addition to promoting growth and remodeling of adult motoneuron innervation, NT-4/5 also potentiates synaptic transmission in developing synapses. Both processes represent mechanisms by which NT-4/5 might indirectly affect muscle fiber phenotype. The overall goal of this project is to determine whether NT-4/5 could act as a retrograde signal in the determination of muscle fiber phenotype.
The specific aims of the proposal are: number 1 Evaluate the influence of exogenous NT-4/5 on the transformation of soleus muscle fibers in neonatal rats, number 2 Determine whether endogenous NT-4/5 is required for the transformation of soleus muscle fibers to occur, and number 3 Determine whether the effect of NT-4/5 is mediated through the central nervous system. The research design and methods are as follows: The left limb of rat neonates will be injected either with, vehicle, NT-4/5, trkB-IgG, or Botlinum toxin and NT-4/5 twice weekly during postnatal development. Animals, in groups of six, will be euthanized at different postnatal ages. Their triceps surae muscles will be harvested bilaterally for immunohistochemistry to compare soleus muscle fiber phenotype. It is anticipated that the results from this project will form the basis for a model of the control of muscle phenotype by a muscle-derived neurotrophin.
|Carrasco, Dario I; English, Arthur W (2003) Neurotrophin 4/5 is required for the normal development of the slow muscle fiber phenotype in the rat soleus. J Exp Biol 206:2191-200|