Defense Date
2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Biomedical Engineering
First Advisor
Michael J. McClure
Second Advisor
Daniel Conway
Third Advisor
Jonathan Isaacs
Fourth Advisor
Zvi Schwartz
Fifth Advisor
Brian Verrelli
Abstract
Despite only comprising 0.1% of the myofiber surface area, a healthy motor endplate is densely packed with acetylcholine receptors (AChRs) responsible for mediating activity between the connected motor neuron and skeletal muscle via the neurotransmitter, acetylcholine. Loss of the endplate, known as fragmentation, is caused by car crashes, deep lacerations, and other traumatic injuries to the innervating nerve or direct injuries to the limb muscle(s) with intramuscular denervation as a common comorbidity. In both cases, endplate fragmentation begins within a week of injury proceeding muscle atrophy causing decreased mobility, paralysis, and quality of life. Endplate fragmentation of intact muscle fibers is recoverable if the motor nerve connection is re-established within an 18-month regenerative window, but many muscles won’t recover before 18 months. However, most patients will still face long term functional deficits due to incomplete regeneration of the muscle tissue including the nerve supply, fibrosis which can inhibit recovery, and dampened neurotransmission caused by fragmented remodeling.
This dissertation addresses the clinical need by investigating the underlying cross-talk signaling between muscle and motor nerve needed preserve the muscle endplate and enhance muscle regeneration. Collectively, these data lay the foundation for further research into muscle-nerve cross-talk and cellular response to nerve derived factors for improved muscle regeneration. Our research findings reveal that apoE3 treatment enhances aneural AChR clustering and further underscores the importance of nerve signaling on myogenesis. Future research hopes to translate these research findings to denervation atrophy caused by traumatic injuries.
Rights
© James Tyr Redden
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
8-8-2024
Included in
Biomaterials Commons, Molecular, Cellular, and Tissue Engineering Commons, Other Biomedical Engineering and Bioengineering Commons