Date of Award

10-30-2020

Publication Type

Master Thesis

Degree Name

M.H.K.

Department

Kinesiology

Keywords

CEP-701, drug repurposing, lestaurtinib, regeneration, skeletal muscle

Supervisor

Matthew Krause

Rights

info:eu-repo/semantics/embargoedAccess

Abstract

Repurposing drugs to enhance skeletal muscle repair mechanisms may unveil novel treatments for certain muscular pathophysiological states while maintaining high safety and efficacy standards at lower costs. The anti-cancer drug lestaurtinib appears to induce fusion and differentiation of myoblasts in vitro, inviting an attempt in the present study to determine if these results are replicable in vivo. To initiate skeletal muscle regeneration, tibialis anterior muscles were injured in both legs of C57BL/6J mice (n = 30) using the myotoxin, cardiotoxin (CTX). At 3 days post-CTX, the affected area on the right leg was treated with lestaurtinib at a concentration of either 40 nM or 200 nM; the left leg was used as a vehicle-treated control. Muscles were excised at either 4, 7, or 14 days post-CTX and then histologically examined to determine the effect of lestaurtinib on muscle regeneration. Fibre cross-sectional area, collagen-positive area (%), embryonic myosin heavy chain (emb-MyHC) positive area (%), and number of emb-MyHC-positive cells were assessed. The regeneration process appeared to be mostly unaffected following lestaurtinib treatment as indicated by no difference in fibre cross-sectional area, number of newly regenerated myofibres, and emb-MyHC-positive area. However, significantly reduced collagen-positive area was observed in lestaurtinib-treated muscle at 7 and 14 days post-CTX. Divergent effects on collagen content were observed between lestaurtinib-treated muscles, suggesting that each drug level exhibited opposing effects on collagen synthesis and/or degradation. These data suggest that single dose treatment of 40 or 200 nM of lestaurtinib at 3 days post-injury does not augment muscle repair, although the 200 nM dose may reduce collagen accumulation. Further investigation of lestaurtinib treatment on muscle regeneration in myopathic states may reveal utility in suppressing muscle fibrosis; however, further study is needed to understand the mechanisms by which lestaurtinib exerts its effects on muscle in vivo.

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