Date of Graduation

2016

Document Type

Thesis

Degree Type

MS

College

School of Medicine

Department

Physiology, Pharmacology & Neuroscience

Committee Chair

Emidio E Pistilli

Committee Co-Chair

Stephen E Alway

Committee Member

Mark I Olfert

Committee Member

Linda Vona-Davis

Abstract

Severe muscle wasting and muscle dysfunction (cachexia) are considered incurable complications associated with a wide variety of chronic diseases. This loss of function and severe wasting causes an increase in fatigue in cancer patients, leading to reduced motivation for daily activities, further reducing prognosis for recovery in these patients leading to a severe increase in morbidity. Recent work from our lab suggests Interleukin-15 (IL-15) induces a pro-oxidative state in the muscle, reducing fatigue and promoting a more oxidative phenotype. One proposed mechanism behind this is the observation that IL-15 promotes mitochondrial biogenesis, lending more mitochondria for oxidative metabolic processes. Therefore, we tested the hypothesis that orthotopic implantation of E0771 mammary tumor cells would induce greater muscle fatigue in tumor bearing mice and that muscle-specific IL-15 overexpression would attenuate this cancer-induced increase in muscle fatigability. In our initial study performed in C57BL/6 wild type mice, 4 weeks of E0771 mammary tumor growth induced a significant increase in muscle fatigue along with a significant reduction in mtDNA content, while 2 weeks of growth had no effects on muscle function. This was associated with lesser mRNA expression for IL-15 and IL-15Ralpha in the muscles of tumor bearing mice. Subsequently, we induced E0771 mammary tumors in muscle-specific IL15 over-expressing mice and littermate control mice for 4 weeks. While muscle fatigue was significantly greater in tumor-bearing littermate control mice compared to littermate control mice without tumors, muscle fatigue was attenuated in muscles from tumor-bearing IL15 over-expressing mice compared to IL15TG mice without tumors. These data highlight IL-15 a potential therapy for reducing fatigue in the weakened/cachectic state. Along with this, IL-15 has been well published with promoting Natural Killer (NK) cell cytotoxicity, increasing immunosurveillance and promoting overall T cell development. This, combine with the pro-oxidative environment make IL-15 an ideal therapy for cancer cachexia. Future studies can look at potential dosing requirements of IL-15 before moving on to clinical trials.

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