Influence of Innervation on Diaphragm Muscle Growth

Mayo Clinic Rochester, Rochester MN

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Abstract

DESCRIPTION (provided by applicant): The proposed studies address very basic questions about the postnatal growth of phrenic motoneurons and diaphragm muscle (DIAm) fibers. Such growth of phrenic motoneurons and DIAm fibers is necessary to meet the increasing functional diversity of the DIAm. The proposed studies will focus on the trophic role of neuregulin (NRG) acting via ErbB receptors in both phrenic motoneurons and DIAm fibers. Our novel and exciting preliminary results raise the intriguing possibility that NRG/ErbB signaling may underlie the postnatal growth of both phrenic motoneurons and DIAm fibers, thereby providing a mechanism by which these essential structural properties of motor units are matched. Accordingly, our first working hypothesis is that NRG/ErbB signaling promotes postnatal growth of phrenic motoneurons (Specific Aims 1 &2). Specific Aim #1: To characterize phrenic motoneuron growth and NRG-1 synaptic input to phrenic motoneurons during postnatal development;Specific Aim #2: To determine the role of NRG/ErbB signaling in growth of phrenic motoneurons during postnatal development. Our second working hypothesis is that NRG/ErbB signaling promotes postnatal growth of DIAm fibers by affecting the balance between protein synthesis and degradation (Specific Aims 3 &4). Specific Aim #3: To determine the effect of NRG/ErbB signaling on DIAm fiber growth during postnatal development;Specific Aim #4: To determine the impact of NRG/ErbB signaling on the balance between protein synthesis and degradation in DIAm fibers during postnatal development The proposed studies will examine postnatal growth of phrenic motoneurons and DIAm fibers. As the most important inspiratory muscle in mammals, the DIAm must provide adequate force to sustain ventilation from birth onwards. It is unique compared to limb muscles, where movement behaviors emerge more gradually after birth. PUBLIC HEALTH RELEVANCE: The diaphragm is the most important inspiratory muscle in mammals as it must provide adequate force to sustain ventilation from birth onwards. It is unique compared to limb muscles, where movement behaviors emerge more gradually after birth. The proposed studies will provide a better understanding of the normal maturation of the diaphragm muscle and the motor neurons that innervate it. In addition, factors that regulate the normal growth and development of the diaphragm will be systematically explored.