Cancer cachexia, the unintentional loss of bodyweight and muscle mass, directly impacts patient survival and quality of life. The role of skeletal muscle in maintaining health, for cancer patients and healthy individuals, involves both the amount of muscle mass and the quality of the muscle, as it relates to metabolic capacity and substrate utilization flexibility. Although understanding muscle mass loss is a major focus of cachexia research, reduced muscle quality likely plays a role in both cachexia progression and mass loss. Understanding how the cancer patient's systemic environment disrupts both muscle metabolism and protein turnover regulation remains a challenge that is substantial enough to have impeded cancer cachexia treatment. Inflammatory cytokine IL-6 and muscle STAT signaling are clear regulators of muscle wasting in tumor-bearing mice. Muscle protein synthesis through mTOR is also suppressed in cachectic muscle. However, significant gaps remain in our understanding of the IL-6 regulation of suppressed muscle anabolic signaling with cancer cachexia. This proposal mechanistically extends our published and preliminary data examining IL-6 regulation of muscle protein turnover during the progression of cachexia. Our long-term goal is to improve cancer patient survival through understanding inflammatory, metabolic and hormonal signaling pathway interactions that disrupt muscle protein synthesis. Our study's overall objective is to mechanistically understand how the IL-6 family of cytokines can regulate nutrient, hormonal, and mechanical control of muscle protein turnover during the initiation and progression of cachexia in ApcMin/+ and Lewis Lung Carcinoma (LLC) implanted mice. Our central hypothesis is that muscle protein synthesis suppression through mTOR signaling is fundamental for cachexia- induced muscle mass loss. The rationale for this proposed research is that the identification of metabolic signaling pathways and the inflammatory regulators of these processes will allow therapeutic countermeasures that can block or reverse the progression of muscle wasting with cancer. Guided by our prior research and preliminary data using ApcMin/+ and LLC mouse cachexia models, we plan to test our central hypothesis and accomplish the objectives of this application with three specific aims: 1) Identify the IL-6 regulation of protein synthesis and mTOR signaling necessary for anabolic resistance to feeding and exercise during the progression of cachexia; 2) Determine if alterations in muscle oxidative metabolism regulate mTOR signaling and protein synthesis during the progression of cachexia; and 3) Determine if suppressed testosterone and androgen-associated signaling regulate mTOR signaling and protein turnover during the progression of cachexia. This research is innovative because it will examine mechanical, metabolic, and hormonal signaling pathways that are regulated by chronic systemic inflammation and control mTOR-signaling regulation of muscle protein synthesis with cachexia. It is significant because the results will lead to developing physical activity and pharmaceutical interventions that can intervene in the progression of muscle wasting with cancer.

Public Health Relevance

Cachexia is a condition of whole body wasting that leads to loss of both muscle and adipose tissue and accounts for 20-40% of cancer-related deaths in the USA. We originally identified increased inflammation related to the underlying cancer as a cause of skeletal muscle loss, and our current proposal seeks to better understand how inflammation induces this loss during the progression of cancer cachexia. Understanding this process should lead to targeted therapies to prevent the progression of cachexia, allowing for the underlying cancer to be treated more effectively and increasing patient survival.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA121249-09
Application #
9439688
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Spalholz, Barbara A
Project Start
2008-05-05
Project End
2019-02-28
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
9
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of South Carolina at Columbia
Department
Other Health Professions
Type
Schools of Public Health
DUNS #
041387846
City
Columbia
State
SC
Country
United States
Zip Code
29208
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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