(PQ 12) The Regulation of Physical Function and Skeletal Muscle Metabolic Signaling After Cessation of 5-Fluorouracil Treatment

(PQ 12) 停止 5-氟尿嘧啶治疗后身体功能和骨骼肌代谢信号的调节

基本信息

批准号：
9927604
负责人：
James A Carson
金额：
$ 15.44万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-08 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9927604
关键词：
Acute Adult Affect Aftercare Aging Body Weight decreased Cachexia Cancer Patient Cancer Survivor Cessation of life Colon Carcinoma Data Development Diagnosis Disease Dose Effectiveness Endocrine Estradiol Exercise Exercise Test Fatigue Female Fluorouracil Functional disorder Future Goals Gonadal Steroid Hormones Guidelines Health Hypogonadism Inflammation Interleukin-6 Investigation Knowledge Leucovorin Malignant Neoplasms Metabolic Metabolic dysfunction Methotrexate Moderate Exercise Molecular Mus Muscle Muscle Fatigue Muscle Mitochondria Muscle function Occupations Outcome Ovarian Patients Physical Function Physical activity Physiological Play Pre-Clinical Model Prevention Property Quality Control Quality of life Recommendation Regimen Regulation Reporting Role Secondary to Sex Differences Signal Transduction Skeletal Muscle Testing Testosterone Toxic effect Withholding Treatment acute toxicity base cancer cachexia cancer therapy chemotherapy colon cancer patients colorectal cancer treatment exercise training gonad function improved irinotecan male muscle metabolism novel oxaliplatin pre-clinical response sex skeletal muscle metabolism skeletal muscle wasting therapeutic target treadmill

项目摘要

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 examination into the existence of sex differences for chemotherapy-induced muscle dysfunction and should provide the rationale for future investigations into exercise and endocrine-based therapies to treat this dysfunction.

成功癌症治疗的中心目标包括增加生存和改善的生活质量。对于大多数大多数结直肠癌（CRC），疲劳和身体功能的改善仍然是挑战治疗完成后的患者。 CRC患者报告的功能降低，导致无法执行与购物，从事体育锻炼和工作有关的日常任务。骨骼肌损失代谢功能障碍在这些负面结果中起关键作用。从历史上看，检查患有癌症的骨骼肌尚未解释化学疗法治疗的作用，而化疗治疗很强改变癌症存活的健康和生活质量的潜力。确定化学疗法如何影响癌症停止治疗后，患者的长期健康和生活质量是一个至关重要的问题。这项拟议的研究与挑衅性的问题12一致：“分子和/或细胞是什么癌症治疗引起的严重不良后遗症发展的机制？问题旨在提高对超出急性毒性的化学疗法并发症的理解但是可以对患者的健康和生活质量产生重大影响。我们试图了解性如何性腺功能和运动（所有调节骨骼肌功能）与化学疗法相互作用。我们的研究将机械检查运动剂量对骨骼肌对化疗的反应的影响。尽管运动是广泛规定的，但运动与化学疗法之间的机械相互作用是理解不佳。我们的研究重点是基于我们的小组和其他拥有的基本发现检查了化学疗法引起的骨骼肌功能的破坏，以及我们引人注目的初步数据这建立了一种新颖的临床前范式来检查性别，性腺功能和运动的影响骨骼肌对FOLFOX或FOLFIRI化学疗法的反应。我们的中心假设是 folfox或folfiri治疗因骨骼肌肉线粒体的破坏而导致持续疲劳小鼠的质量控制，可以通过低剂量的跑步机锻炼来救出，并因女性而加剧性腺功能障碍。我们预计化学疗法对骨骼肌的影响是性别依赖性的，因为性卵巢功能会影响肌肉代谢，注射和IL-6敏感性。具体目标1将确定运动剂量对骨骼肌疲劳和线粒体的FOLFOX或FOLFIRI调节的影响男性和雌性小鼠的质量控制。基于建议的三个跑步机锻炼剂量对于癌症的存活率将进行检查。特定目标2将调查性腺功能障碍的骨骼调节 FOLFOX或FOLFIRI治疗的肌肉疲劳和线粒体质量控制，并确定性别是否管理可以修改这些结果。我们的研究提供了对存在的重要初步检查化学疗法引起的肌肉功能障碍的性别差异，并应为未来提供理由对治疗这种功能障碍的运动和基于内分泌的疗法的调查。