Effects of Aerobic Exercise on Skeletal Muscle Remodeling in Colon Cancer

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PROJECT SUMMARY/ABSTRACT Postdiagnosis physical activity is associated with a lower risk of cancer recurrence and death in colon cancer survivors. However, the biological mechanisms that underpin the effects of physical activity on cancer recurrence and death are poorly understood. Skeletal muscle is the most abundant tissue in the human body, representing 40% of body weight and 30% of basal energy expenditure. Skeletal muscle fat infiltration, known as myosteatosis, is an ectopic triglyceride depot that causes insulin resistance and inflammation. One in three colon cancer survivors has myosteatosis. Myosteatosis increases the risk of cancer recurrence, cardiovascular disease, and death in colon cancer survivors. Among older adults, myosteatosis predicts poor muscle strength and subsequent disability, which is relevant because 62% of colon cancer survivors have functional limitations, and these limitations erode quality of life and compromise longevity. We hypothesize that structured exercise training remodels skeletal muscle composition (Aim 1), corrects muscle metabolic inflexibility (Aim 2), and increases muscle function (Aim 3) in a manner consistent with an improved cancer prognosis and reduced risk of competing morbidity and mortality. In response to PAR-18-893 "Physical Activity and Weight Control Interventions Among Cancer Survivors: Effects on Biomarkers of Prognosis and Survival," we will conduct a randomized controlled trial of structured aerobic exercise training in 138 stage I-III colon cancer survivors. Subjects will be recruited using the Louisiana Tumor Registry, a population-based registry funded by the NCI’s Surveillance, Epidemiology and End Results (SEER) Program to reflect the socioeconomic diversity of the region. Subjects will be randomized to stretching attention control or 225 min/wk of moderate-intensity aerobic exercise (70% heart rate reserve) for 12-weeks. Aim 1 will test the hypothesis that aerobic exercise decreases whole-body intermuscular adipose tissue measured using whole-body magnetic resonance imaging. Aim 2 will test the hypothesis that aerobic exercise decreases postprandial triglyceride concentration and increases free fatty acid oxidation measured using an isotopically labeled liquid mixed meal containing [U-13C]palmitate. Aim 3 will test the hypothesis that aerobic exercise increases lower extremity skeletal muscle strength and physical function using Biodex dynamometry and 10-step stair climb power. Myosteatosis is common and compromises the health of colon cancer survivors. Identifying the health-promoting mechanisms of physical activity would facilitate precision exercise prescriptions that are patient-centered and proven to have a high probability of clinical benefit. The proposed aims will leverage a transdisciplinary team's synergies to offer comprehensive and definitive insight into a novel biological mechanism of physical activity and cancer prognosis at the junction of muscle physiology and adipocyte biology.