First Advisor

Hydock, David S.

Document Type

Dissertation

Date Created

8-2019

Abstract

Doxorubicin (Dox) is a widely used anthracycline antibiotic used to treat a number of hematological and solid tumor cancers. Dosage however, is limited due to its toxic effects in healthy tissues. Negative consequences include myotoxicity in skeletal muscle, which may limit mobility and activities of daily living. Doxorubicin increases the formation of reactive oxygen species, which triggers apoptosis in the tumor and healthy tissue. Skeletal muscle undergoes apoptosis in response to Dox treatment, via the activation of the cleaved caspase-3 and its downstream target, poly(ADP-ribose) polymerase. Creatine monohydrate (Cr), a naturally occurring chemical, when taken exogenously, can improve athletic performance. Recently, it has been shown that Cr can positively impact several diseases and act as a antioxidant, capable of scavenging free radicals and reducing apoptosis. Purpose: To determine the effect of two types of Cr feeding and Dox administration on skeletal muscle apoptotic proteins at two separate time points. Methods: Ten week old male Sprague-Dawley rats were randomly assigned to one of six groups: control + saline (Con-Sal, n=10), control + doxorubicin (Con-Dox, n=10), creatine 1 + saline (C1-Sal, n=10), creatine 1 + doxorubicin (C1-Dox, n=10), creatine 2 + saline (C2-Sal, n=10), creatine 2 + doxorubicin (C2-Dox, n=10). Animals were fed for four weeks and were injected with a bolus 15 mg/kg i.p. injection of Dox or Sal and sacrificed either 1-day or 3-days post injection. Post injection, the extensor digitorum longus (EDL), soleus (SOL), and diaphragm (DIA) were excised and Western blotting for expression of cleaved PARP, caspase-3, and cleaved caspase-3 was conducted. Creatine concentration was also analyzed using a commercially available assay kit. Results: A main drug effect was observed, with increased levels of apoptosis observed in the 1-day EDL, SOL, and in the 3-day EDL. Equally, a main drug effect was observed, with decreased caspase-3 levels in the 3-day SOL, and cleaved PARP levels in the 3-day DIA. There was a diet effect, with increased cleaved PARP levels in the 1-day EDL, SOL, and cleaved caspase-3 levels in the 3-day EDL. An equal diet effect was detected, with decreased caspase-3 levels in the 1-day EDL and cleaved caspase-3 levels in the 1-day SOL and DIA. The 1-day SOL had lower creatine concentration with Dox administration and the 3-day EDL had decreased Cr concentrations with both Dox administration and Cr feeding. Conclusion: Doxorubicin had the largest impact on apoptosis in the EDL, suggesting Dox’s effects on apoptosis may differ between tissue. Creatine concentration in the EDL was lower in animals receiving Dox, and this was not observed in the DIA, supporting the idea that Dox toxicity may differ between tissue.

Extent

121 pages

Local Identifiers

Torok_unco_0161D_10746.pdf

Rights Statement

Copyright is held by the author.

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