Date of Graduation

5-2021

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

Gray, Michelle

Keywords

Activin receptor type-2B (ACVR2B); Growth factor receptor-bound protein 10 (GRB10); muscle atrophy; prevention

Abstract

Background: Muscle atrophy is the shrinkage of muscle fibers that are largely maintained by a balance of protein synthesis and degradation. Imbalances in protein synthesis and degradation are observed in different muscle atrophy disorders such as cancer cachexia and disuse. These forms of muscle atrophy produce distinct wasting pathologies that are influenced by biological sex. Activin receptor type-2B (ACVR2B) and Growth factor receptor-bound protein 10 (GRB10) have been identified as genes that potentially regulate muscle mass while also displaying sexually dimorphic differences. Purpose: To examine the influence of ACVR2B and GRB10 throughout the development of cancer cachexia and disuse-induced atrophy in male and female mice. Methods: Lewis Lung Carcinoma (LLC) was injected into the hind flank of male and female C57BL6/J mice at 8 weeks of age. Tumors were allowed to develop for 1, 2, 3, or 4 weeks and were compared to a PBS control. Disuse-induced male and female C57BL6/J mice were hindlimb unloaded for 24 hours, 48 hours, 72 hours, and 168 hours and were compared to cage control mice. RT-qPCR was used to measure mRNA content of ACVR2B and GRB10 of the gastrocnemius muscle. Results: LLC female mice had ~35% lower ACVR2B mRNA content compared to PBS control with a ~40% and ~30% lower content at LT and HT compared to 2-week LLC animals (p<0.05). LLC male ACVR2B mRNA contents were significantly lower by ~48%, ~56%, and ~36% at one, two, and four weeks, respectively, of tumor-bearing compared to PBS control mice (p=0.0006). No significant differences were observed in GRB10 mRNA content in LLC female mice across all cohorts. GRB10 mRNA content in LLC males was significantly lower by ~41% after one week of tumor implantation compared to LLC PBS control mice (p=0.0094). ACVR2B mRNA content in HU female mice was not significantly different across all cohorts (p=0.192). HU males displayed a ~two-fold lower ACVR2B mRNA content after 3 days compared to cage control mice (p=0.0233) and 7 days of unloading (p=0.015). GRB10 mRNA content in HU males was significantly lower at 2 and 3 days with a ~51% lower content compared to control mice with also a ~two-fold decrease compared to 7 days of hindlimb unloading. Conclusions: ACVR2B and GRB10 content displayed differential responses during cancer cachexia and disuse-induced muscle atrophy that varied by sex. Data suggests that ACVR2B and GRB10 play a greater role in males during muscle atrophy than compared to females. Future experiments incorporating additional muscle groups are warranted to better understand the pathways of ACVR2B and GRB10 and their influence between sexes during cancer cachexia and disuse.

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