Date of Graduation

5-2019

Document Type

Thesis

Degree Name

Master of Science in Kinesiology (MS)

Degree Level

Graduate

Department

Health, Human Performance and Recreation

Advisor/Mentor

Greene, Nicholas P.

Committee Member

Washington, Tyrone A.

Second Committee Member

Dridi, Sami

Keywords

Cancer Cachexia; Hindlimb-Unloading; Muscle Atrophy; Plasma; Proteomics

Abstract

Introduction: Muscle atrophy results from a dysfunction in protein turnover that leads to loss of mass and function and occurs concurrently with multiple pathologies such as cancer and extended bed rest. Atrophy reduces overall quality of life while increasing morbidity and mortality. Currently, efficacious therapeutic interventions to treat and prevent muscle wasting in all its forms are lacking, however if conserved mechanisms can be identified between wasting conditions, this would aid in the development of multipurpose therapeutics to ameliorate this pathology. Purpose: To examine circulating factors present across atrophic pathologies. Methods: 35 male C57BL/6J mice were assigned to hindlimb unloading (HU), Lewis Lung Carcinoma (LLC), or control groups. HU animals were hindlimb-unloaded for 1 week to induce disuse atrophy. LLC cells were injected into the right hind-flank to induce cancer cachexia. Tumors developed for approximately 4 weeks. Age-matched mice were humanely euthanized after experimental intervention. Muscle and plasma were collected for analysis. Plasma was analyzed by tandem mass tag (TMT) proteomics. Results: Raw plantaris weight was significantly lower in LLC (22.7%) and HU (18.6%) groups compared to control (p<0.05), but not different from each other (p>0.05). Equivalent tibia sizes across groups suggest no significant differences in body size. In the LLC-HU comparison, 104 proteins were differentially expressed (DE). 44 were up-regulated and 60 were down-regulated. In the LLC-CON comparison, 91 DE proteins were observed. Of these, 39 were up-regulated and 52 were down-regulated. In the HU-CON comparison, 5 DE proteins were up-regulated and 4 were down-regulated; a total of 9 DE proteins were observed. Several signaling pathways were implicated in this analysis including the acute phase response signaling system and liver X receptor/retinoid X receptor (LXR/RXR) and farnesoid X receptor/retinoid X receptor (FXR/RXR) activation. Conclusion: Plasma proteomic profiles are altered in cancer cachexia and disuse-induced atrophy. Modulated protein profiles suggest the possibility of multi-tissue involvement in muscle atrophy. Future experiments are required to understand how plasma proteins and muscle interact and to determine the mechanisms of possible novel atrokines observed herein.

Download

Share

COinS