Cancer cachexia severely depletes skeletal muscle mass leading to impairments in physical function and a diminished quality of life. In the clinical realm, malnutrition and cachexia are synonymous. However, cachexia is more complex than mere caloric deficiency, since improving nutritional status does not reverse or prevent muscle wasting. Our preliminary data show that the response of skeletal muscle protein to the anabolic stimulus of amino acids is impaired in cancer patients. We propose that the dysregulation of skeletal muscle protein balance in cancer patients is altered by persistent systemic and localized skeletal muscle inflammation derived from tumoral and humoral catabolic factors. Specifically, these factors alter the regulation of muscle protein balance by affecting both synthesis and breakdown. Synthesis is affected because catabolic factors diminish the plasma concentrations of key branched-chain amino acids such as leucine, thereby suppressing the stimulus for nutrition-derived anabolism. Breakdown is affected because catabolic factors such as tumor necrosis factor-? (TNF-?) enhance nuclear factor-?B (NF-?B), which in turn activates muscle proteolysis via the ubiquitin-proteasome system. Our data demonstrate that skeletal muscle in cancer patients exhibits increased activation of NF-?B and enhanced inflammatory burden. More recently, we found that 3 months of testosterone therapy downregulates ubiquitin and the E3 ubiquitin ligases MuRF1 and MAFbx/Atrogin-1 gene expression along with blocking cleavage of a novel 14-kD actin fragment in the initial step of actomyosin destruction. Our general hypothesis is that the antianorectic and anticachectic effects of leucine-enhanced essential amino acids (L-EAA) supplemented concomitantly with testosterone's anabolic and anticatabolic properties will enhance lean muscle mass in patients with advanced (stages IIB, IIIA and IIIB) or recurrent cervical carcinoma by increasing the stimulus for protein synthesis, and by inhibiting the activation of muscle proteolysis, respectively. We will conduct a randomized, double-blind, placebo-controlled intervention study designed to clinically and mechanistically assess novel nutritional (L-EAA) and pharmacologic (testosterone) therapies aimed at preventing or normalizing cancer-related muscle wasting in conjunction with standard of care (SOC) treatment. We will determine the efficacy of this novel therapeutic approach on the following outcome measures in patients with advanced or recurrent cervical carcinoma: 1) lean body mass and muscle strength, 2) muscle protein turnover, and 3) inflammatory biomarkers and signaling pathways of atrophy in skeletal muscle. Project Narrative Cervical cancer is the second most prevalent cancer in women, with 470,000 new cases occurring globally each year. This study will test whether nutrition and hormones can prevent cancer-related muscle loss. Our study is important because extreme muscle loss is responsible for at least 20% of all cancer deaths. Results from this study may lead to better ways of preventing cancer-related weight loss, and improve the quality of life and survival of those affected by cervical cancer.

Public Health Relevance

Cervical cancer is the second most prevalent cancer in women, with 470,000 new cases occurring globally each year. This study will test whether nutrition and hormones can prevent cancer-related muscle loss. Our study is important because extreme muscle loss is responsible for at least 20% of all cancer deaths. Results from this study may lead to better ways of preventing cancer-related weight loss, and improve the quality of life and survival of those affected by cervical cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA127971-06
Application #
8433448
Study Section
Special Emphasis Panel (ZRG1-MOSS-H (03))
Program Officer
Kim, Young S
Project Start
2008-04-18
Project End
2014-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
6
Fiscal Year
2013
Total Cost
$252,099
Indirect Cost
$81,971
Name
University of Texas Medical Br Galveston
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
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Fitts, Robert H; Peters, James R; Dillon, E Lichar et al. (2015) Weekly versus monthly testosterone administration on fast and slow skeletal muscle fibers in older adult males. J Clin Endocrinol Metab 100:E223-31
Porter, Craig; Hurren, Nicholas M; Cotter, Matthew V et al. (2015) Mitochondrial respiratory capacity and coupling control decline with age in human skeletal muscle. Am J Physiol Endocrinol Metab 309:E224-32
Sinthujaroen, Patuma; Wanachottrakul, Nattaporn; Pinkaew, Decha et al. (2014) Elevation of serum fortilin levels is specific for apoptosis and signifies cell death in vivo. BBA Clin 2:103-111
Urban, Randall J; Dillon, E L; Choudhary, S et al. (2014) Translational studies in older men using testosterone to treat sarcopenia. Trans Am Clin Climatol Assoc 125:27-42; discussion 42-4
Zgaljardic, Dennis J; Durham, William J; Mossberg, Kurt A et al. (2014) Neuropsychological and physiological correlates of fatigue following traumatic brain injury. Brain Inj 28:389-97
Sheffield-Moore, Melinda; Wiktorowicz, John E; Soman, Kizhake V et al. (2013) Sildenafil increases muscle protein synthesis and reduces muscle fatigue. Clin Transl Sci 6:463-8
Dillon, E Lichar (2013) Nutritionally essential amino acids and metabolic signaling in aging. Amino Acids 45:431-41
Horstman, Astrid M; Dillon, E Lichar; Urban, Randall J et al. (2012) The role of androgens and estrogens on healthy aging and longevity. J Gerontol A Biol Sci Med Sci 67:1140-52
Casperson, Shanon L; Sheffield-Moore, Melinda; Hewlings, Susan J et al. (2012) Leucine supplementation chronically improves muscle protein synthesis in older adults consuming the RDA for protein. Clin Nutr 31:512-9

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