This project is concerned with defining the role of the motor neuron in directing the biochemical differentiation of developing skeletal muscle. Mature skeletal muscle is composed of heterogeneous fibers that vary in biochemical, histochemical, contractile, and morphological characteristics, and it is well recognized that the motor neuron regulates the maintenance and plasticity of these fiber type characteristics. Whether the motor neuron exerts a similar influence on the differentiation of developing skeletal muscle fibers is unknown. The experimental approach involves examination of the in vivo developmental differentiation of two biochemical systems: enzymes in pathways for energy production and contractile protein isozymes at the level of single muscle fibers using quantitative microchemical and micro two-dimensional gel electrophoretic techniques. Two specific questions will be studied in developing rat skeletal muscle. First, what is the time course for differentiation of these two biochemical systems in normal skeletal muscle, and is there a correlation between the developmental transitions of these two systems? Secondly, with experimental manipulation of the pattern of motor neuron innervation, are there changes in the timing and extent of biochemical differentiation? The results of these experiments will be used to provide the foundation for examination of a third question, are there specific human neuromuscular diseases where there is a delay or arrest in the process of developmental differentiation? This study of developmental nerve-muscle interactions offers an opportunity to examine the influence of the nervous system on the development and differentiation of a post-synaptic target. The extension of this proposal to the examination of human neuromuscular diseases will enhance understanding of the pathophysiology of these diseases. This may result in improved methods for diagnosis and provide a basis for rational modes of therapeutic intervention in these currently untreatable diseases.
