Title

Analysis of Botulinum Toxin A and Interacting Proteins in Skeletal Muscle Cells: An Investigation into the Mechanisms of Botulinum Toxin A as a Treatment for Chronic Exertional Compartment Syndrome

Date of Award

Summer 2021

Degree Type

Thesis

Department

Chemistry

First Advisor

Dr. Willa Harper

Second Advisor

Dr. Bruce Heyen

Abstract

Background: Chronic exertional compartment syndrome (CECS) is a condition in which muscle tissue expands against the surrounding fascia during activity and is compressed along with the nerves and blood vessels within the muscle compartment, leading to abnormally high intracompartmental pressure (ICP) and debilitating pain. Treatment typically includes fasciotomy, which results in significant levels of CECS recurrence; however, botulinum toxin A (BoNT-A) injection has recently been seen to decrease both ICP and pain through an unknown mechanism with little to no recurrence.

Methods: In this study, cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), prostaglandin E2 receptor 4 (EP4), endothelial nitric oxide synthase (eNOS), and inducible nitric oxide synthase (iNOS) were analyzed with either BoNT-A light chain or heavy chain through docking models via PyRosetta. These studies were performed in order to determine their probability of interaction.

Results: The EP4/BoNT-A heavy chain combination was found to have reaction scores most comparable to known interactions of BoNT-A in neural cells. In accordance with this finding, levels of cyclic adenosine monophosphate (cAMP), a downstream effector of EP4, consistently increased in myoblasts treated with BoNT-A.

Conclusion: Altogether, these data uncover an area of future research in determining the interaction of BoNT-A and the EP4 pathway in muscle cells, as well as the implications this may have on CECS and its treatment.

Comments

This poster describes work completed for the Pence-Boyce Summer Research Program. The thesis will be posted with the University Honors Program.

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