Central objectives for successful cancer treatment include increased survival and improved quality of life. Increased fatigue and decreased physical function remain challenges for most colorectal cancer (CRC) patients after the completion of treatment. CRC patients report functional decrements that cause an inability to perform daily tasks related to shopping, engaging in physical activity, and holding a job. Skeletal muscle loss and metabolic dysfunction play a critical role in these negative outcomes. Historically, the examination of skeletal muscle with cancer has not accounted for the effect of chemotherapy treatment, which has strong potential to alter the health and life quality of cancer survivors. Determining how chemotherapy impacts cancer patients’ long–term health and quality of life after the cessation of treatment is a critically significant question. This proposed study is aligned with Provocative Question 12, “What are the molecular and/or cellular mechanisms that underlie the development of cancer therapy-induced severe adverse sequelae?” This question seeks to improve the understanding of chemotherapy complications that extend beyond acute toxicity but can have significant ramifications for patient health and life quality. We seek to understand how sex, gonadal function, and exercise, all of which regulate skeletal muscle function, interact with chemotherapy. Our study will mechanistically examine the effect of exercise dose on skeletal muscle’s response to chemotherapy. Although exercise is widely prescribed, the mechanistic interaction between exercise and chemotherapy is poorly understood. Our study’s focus is based on fundamental discoveries by our group and others who have examined chemotherapy-induced disruptions to skeletal muscle function, and our compelling preliminary data that establishes a novel preclinical paradigm to examine the effects of sex, gonadal function, and exercise dose on skeletal muscle’s response to either Folfox or Folfiri chemotherapy. Our central hypothesis is that either Folfox or Folfiri treatment cause lasting fatigue through the disruption of skeletal muscle mitochondrial quality control in mice, which can be rescued by low dose treadmill exercise and is exacerbated by female gonadal dysfunction. We expect that chemotherapy effects on skeletal muscle are sex dependent, since sex and ovarian function can affect muscle metabolism, inflammation, and IL-6 sensitivity. Specific aim 1 will determine the effect of exercise dose on Folfox or Folfiri regulation of skeletal muscle fatigue and mitochondria quality control in male and female mice. Three treadmill exercise doses that are based on recommendations for cancer survivors will be examined. Specific aim 2 will investigate hypogonadism’s regulation of skeletal muscle fatigue and mitochondria quality control by Folfox or Folfiri treatments and determine if sex hormone administration can modify these outcomes. Our study provides a critical initial exam...