Graduation Year

2019

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Medical Sciences

Major Professor

Dominic P. D'Agostino, Ph.D.

Committee Member

Jerome Breslin, Ph.D.

Committee Member

Nagi Kumar, Ph.D.

Committee Member

Gina DeNicola, Ph.D.

Committee Member

Joshua Scallan, Ph.D.

Keywords

Atrophy, Cancer Cachexia, Skeletal Muscle, Ketone Bodies

Abstract

Cancer anorexia cachexia syndrome (CACS) is a distinct atrophy disease negatively influencing multiple aspects of clinical care and patient quality of life. Although it directly causes 20% of all cancer-related deaths, there are currently no model systems that encompass the entire multifaceted syndrome, nor are there any effective therapeutic treatments. Here, we show that the VM-M3 mouse model of systemic metastasis demonstrates a novel, immunocompetent, logistically feasible, repeatable phenotype with progressive tumor growth, spontaneous metastatic spread, and the full multifaceted CACS with expected sex dimorphisms across tissue wasting. We also demonstrate that the ubiquitin proteasomal degradation pathway was significantly upregulated in association with reduced IGF-1/Insulin and increased FOXO3a activation, but not TNF-α-induced NF-κB activation, driving skeletal muscle atrophy. Additionally, we show that R/S 1,3-butanediol acetoacetate diester (Ketone Diester; KDE) administration shifted systemic metabolism, attenuated tumor burden, reduced tissue catabolism, and mitigated comorbid symptoms in both CACS and cancer-independent atrophy environments. Our findings suggest the ketone diester attenuates multifactorial CACS skeletal muscle atrophy and inflammation-induced tissue catabolism, demonstrating anti-catabolic effects of ketones bodies in multifactorial atrophy.

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