Cachexia is a condition of whole body wasting that accounts for 20-40% of all cancer-related deaths, particularly GI tract and lung cancers. Inflammatory cytokines are significant effectors of skeletal muscle loss, and the cytokine IL-6 has gained notoriety as a signaling molecule involved in cachexia. Mice heterozygous for a mutated Apc gene (ApcMin/+) develop a significant intestinal polyp burden by 10 weeks of age and become cachexic between 18 and 26 weeks of age. The use of this mouse for studying the regulation of cachexia is novel, and has advantages compared to other animal models of cachexia, including a slower rate of wasting and lack of anorexia. The PI has shown that the inflammatory cytokine IL-6 is a modulator of cachexia in the ApcMin/+ mouse. Knockout of IL-6 prevents cachexia, while over-expression of IL-6 accelerates cachexia. It is not yet clear whether IL-6 exerts a direct effect on muscle or an indirect affect, by affecting tumor growth or secretion of a cachexic mediator of tumor origin. However, understanding the beneficial effects of IL-6 ablation will clearly provide insight into the relationships between inflammation and cachexia during cancer. The overall purpose of this application is to address mechanisms underlying cachexia in the ApcMin/+ mouse. These mechanisms will be examined in respect to the initial and severe stages of wasting and the muscle's oxidative metabolism capacity.
Aim 1 will characterize the regulation of muscle protein synthesis and proteasomal degradation during the early and severe stages of wasting in the cachexic ApcMin/+ mouse. Differential regulation of these processes in glycolytic and oxidative muscle during the progression of cachexia will be examined. Experiments also will examine graded increases in circulating IL-6 on muscle protein synthesis and degradation.
Aim 2 will characterize the regulation of muscle mitochondrial function, and myonuclear apoptosis during the early and severe stages of wasting in the ApcMin/+ mouse. Biomarkers of muscle oxidative stress, protein chemical modification, mitochondria uncoupling, mitochondrial number, and indices of apoptosis in glycolytic and oxidative muscle will be assessed during the progression of cachexia and with graded IL-6 over- expression.
Aim 3 will determine if direct signaling through the muscle gp130 receptor regulates muscle protein turnover, mitochondrial function and apoptosis in the ApcMin/+ mouse. These studies will use a muscle-specific cre-lox system to decrease gp130 receptor expression in a tissue-specific manner in order to determine whether the permissive effect of IL-6 on cachexia is a direct effect on muscle metabolism or an indirect effect resulting from tumor growth or inflammation, in general.
. Completion of this work will lead to a better understanding of the role of systemic IL-6 signaling for the regulation of severe muscle wasting with cachexia. The identification of potential targets for therapeutic countermeasures to both treat and prevent the severe stages of wasting should allow patients to better tolerate and respond to treatments for the underlying cancer condition, thus improving mortality and morbidity
| VanderVeen, Brandon N; Hardee, Justin P; Fix, Dennis K et al. (2018) Skeletal muscle function during the progression of cancer cachexia in the male ApcMin/+ mouse. J Appl Physiol (1985) 124:684-695 |
| Montalvo, Ryan N; Counts, Brittany R; Carson, James A (2018) Understanding sex differences in the regulation of cancer-induced muscle wasting. Curr Opin Support Palliat Care 12:394-403 |
| Hardee, Justin P; Counts, Brittany R; Gao, Song et al. (2018) Inflammatory signalling regulates eccentric contraction-induced protein synthesis in cachectic skeletal muscle. J Cachexia Sarcopenia Muscle 9:369-383 |
| Montalvo, Ryan N; Hardee, Justin P; VanderVeen, Brandon N et al. (2018) Resistance Exercise's Ability to Reverse Cancer-Induced Anabolic Resistance. Exerc Sport Sci Rev 46:247-253 |
| Brown, Jacob L; Rosa-Caldwell, Megan E; Lee, David E et al. (2017) Mitochondrial degeneration precedes the development of muscle atrophy in progression of cancer cachexia in tumour-bearing mice. J Cachexia Sarcopenia Muscle 8:926-938 |
| Hetzler, Kimbell L; Hardee, Justin P; LaVoie, Holly A et al. (2017) Ovarian function's role during cancer cachexia progression in the female mouse. Am J Physiol Endocrinol Metab 312:E447-E459 |
| Hardee, Justin P; Carson, James A (2017) Understanding Sarcopenia Development: A Role for Healthy Behaviors. Am J Lifestyle Med 11:17-20 |
| Hardee, Justin P; Montalvo, Ryan N; Carson, James A (2017) Linking Cancer Cachexia-Induced Anabolic Resistance to Skeletal Muscle Oxidative Metabolism. Oxid Med Cell Longev 2017:8018197 |
| Gao, Song; Durstine, J Larry; Koh, Ho-Jin et al. (2017) Acute myotube protein synthesis regulation by IL-6-related cytokines. Am J Physiol Cell Physiol 313:C487-C500 |
| Fix, Dennis K; Hardee, Justin P; Bateman, Ted A et al. (2016) Effect of irradiation on Akt signaling in atrophying skeletal muscle. J Appl Physiol (1985) 121:917-924 |
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