First Advisor

Hydock, David S.

Date Created

8-2019

Abstract

Doxorubicin (DOX) is a highly potent chemotherapy drug that impacts the entire body rather than a targeted treatment area. While DOX treatment assists in the disruption and prevention of certain types of cancer growth, it damages many physiological processes in the body that were functioning normally and otherwise healthy prior to its administration. Damage induced by DOX on organ functioning can lead to other malignancies in the body, such as cachexia, cardiotoxicity, and myotoxicity, among others. Skeletal muscle relies on myogenic regulatory factors (MRFs), transcription factors expressed by satellite cells, for positive regulation of phases of muscle development and response to damage. In skeletal muscle, DOX administration has caused decreased MRF levels as well as increased myostatin and ubiquitin ligase expression, which are negative regulators of muscle mass. Previous findings have reported altered regulatory protein expression and shifts in muscle fiber characteristics of the diaphragm (DIA), as well as decline in patient respiratory function, following DOX treatment. Creatine monohydrate (Cr) supplementation prior to DOX administration has protected skeletal muscle against DOX-induced dysfunction, damage, and decline in MRF expression. However, the effects of DOX treatment in combination with Cr supplementation on the expression of proteins that negatively regulate muscle mass, such as myostatin and MuRF-1, in the DIA have yet to be investigated. PURPOSE: To investigate the effects of in vivo DOX administration, following the completion of two Cr supplementation protocols, on the expression of negative regulators of skeletal muscle mass, myostatin and MuRF-1, in the DIA tissue of rats sacrificed one- and three-days post-injection (N=115). METHODS: Male Sprague-Dawley rats were fed a diet supplemented with a standard Cr dosage of 2% for four weeks (CrS), a Cr loading dosage of 4% for one week and 2% for three weeks (CrL), or a standard control (CON) diet for four weeks. Based on random assignment, animals received an intraperitoneal injection of DOX (15 mg/kg) or saline (SAL) of the same volume and underwent anesthesia one- or three-days post-injection. Following DIA removal, Western blotting was used to quantify the protein expression of myostatin and MuRF-1. RESULTS: In the DIA, there was no significant diet effect, drug effect, or interaction at the one-day timepoint relating to myostatin expression (p = 0.255, p = 0.412, p = 0.770, respectively). There was also no diet effect, drug effect, or interaction pertaining to myostatin expression in the DIA at the three-day timepoint. (p = 0.710, p = 0.935, p = 0.566, respectively). In the DIA, there was no significant diet effect, drug effect, or interaction at the one-day timepoint pertaining to the expression of MuRF-1 (p = 0.772, p = 0.248, p = 0.137, respectively). There also was no diet effect, drug effect, or interaction relating to MuRF-1 expression in the DIA at the three-day timepoint (p = 0.826, p = 0.931, p = 0.941, respectively). CONCLUSION: There were no significant diet effects, drug effects, or interactions at either timepoint among myostatin and MuRF 1 protein expression in the DIA as determined by two-way ANOVA (p > 0.05). These findings suggest that mediators and mechanisms unrelated to myostatin and MuRF-1 protein expression may contribute to the decline in respiratory function commonly observed in individuals undergoing chemotherapy treatment.

Extent

109 pages

Local Identifiers

ShepardThesis2019

Rights Statement

Copyright is held by the author.

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