Impact of obesity on chemotherapy-induced muscle mitochondrial dysfunction

肥胖对化疗引起的肌肉线粒体功能障碍的影响

基本信息

批准号：
10752436
负责人：
Thomas Cardaci
金额：
$ 3.71万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10752436
关键词：
Activities of Daily Living Animal Cancer Model Antioxidants Biogenesis Body Surface Area Body Weight Body mass index C26 tumor Cachexia Cancer Patient Cancer Prognosis Cancer Survivorship Colorectal Data Dependence Development Diet Dietary Practices Dihydropyrimidine Dehydrogenase Disease Dose Drug toxicity Enzymes Epidemiology Fatigue Fluorouracil Functional disorder Goals Half-Life Health Knowledge Literature Liver Maintenance Malignant Neoplasms Metabolic Metabolic dysfunction Metabolism Mitochondria Modeling Morbidity - disease rate Morphology Mus Muscle Mitochondria Muscle function Natural Compound Natural Products Obese Mice Obesity Pathology Patients Pharmaceutical Preparations Phenotype Positioning Attribute Postdoctoral Fellow Process Publishing Quality Control Quality of life Quercetin Recommendation Recording of previous events Regimen Research Respiration Role Skeletal Muscle Source Testing Therapeutic Thinness Toxic effect Training Transgenic Mice Treatment Efficacy Treatment outcome Weight anti-cancer cancer cachexia cancer risk cancer therapy carcinogenesis chemotherapy dietary dietary antioxidant dietary approach improved insight loss of function mitochondrial dysfunction muscle form novel obese person obesity treatment pharmacologic prevent protein degradation tumor

项目摘要

PROJECT SUMMARY Obesity increases the risk of cancer; thus, individuals that are obese are more likely to undergo chemotherapy in their lifetime. However, there is a dearth of literature on the impact of weight status on cancer patient life quality and functional capacity throughout treatment. For instance, our knowledge of the impact of obesity on cancer and chemotherapy-induced cachexia - the unintentional loss of lean mass, which directly contributes to functional dependency, poor treatment outcomes, and decreased survival – is incomplete. An “obesity paradox” has been postulated; however, the epidemiology remains equivocal on the benefits/detriments of a high pre-treatment body weight and body mass index. While obesity and cachexia are diseases at opposite ends of the weight spectrum, these pathologies share some underlying perturbations (e.g. mitochondrial dysfunction) that may exacerbate functional decrements when these morbidities co-occur. Our lab made the novel and significant discovery that obese mice, dosed for lean mass, were unable to survive 2-3 cycles of the chemotherapeutic, 5 fluorouracil (5FU). Indeed, contrary to what has been suggested, we discovered that obese mice are not protected against chemotherapy-induced cachexia and show exacerbated skeletal muscle toxicities. Disruptions to mitochondria are 1) central to chemotherapy-induced skeletal muscle mass loss, and 2) are known to be existent with obesity and metabolic dysfunction; however, mitochondrial dysfunction and resultant functional deficits have not been assessed when these morbidities co-occur. Antioxidants have been shown to improve mitochondrial function. Indeed, we have shown that the antioxidant dietary compound, quercetin, can reduce cancer, cancer cachexia, and chemotherapy-induced fatigue, and can increase mitochondrial function in healthy mice. Thus, quercetin may hold promise as a dietary strategy to treat cachexia associated with cancer and its therapies in the obese condition. The primary goal of my proposed F31 is to 1) understand the impact of obesity on 5FU-induced skeletal muscle dysfunction and 2) provide mechanistic and therapeutic insights aimed at better improving 5FU tolerance with obesity. My central hypothesis is that 5FU-induced mitochondrial loss and dysfunction is exacerbated with an obese phenotype and intervening with quercetin will mitigate the deleterious effects of 5FU on skeletal muscle. To test this hypothesis, I propose three related but independent specific aims: 1) Examine the impact of obesity on cancer and 5FU-induced cachexia and function loss; 2) Determine the role of mitochondria in obesity-exacerbated 5FU toxicities; and 3) Explore the utility of dietary quercetin on improving 5FU treatment tolerance and off- target toxicities with obesity. The proposed studies align with my training aims and will provide me with the opportunity to gain expertise in obesity phenotyping and natural compounds as therapeutics, mitochondrial health and dynamics, cachexia and functional testing. Further, the professional development training will promote advancement to the next step in my path to research independence.

项目摘要肥胖增加了癌症的风险；因此，肥胖的个体更有可能接受化学疗法在他们的一生中。但是，文献关于体重状况对癌症患者生活的影响而死亡整个治疗过程中的质量和功能能力。例如，我们了解肥胖对癌症和化学疗法引起的恶病质 - 瘦质量的无意损失，直接有助于功能依赖性，治疗效果不佳和生存降低 - 不完整。 “肥胖悖论已被假设；但是，流行病学仍然等同于高预处理体重和体重指数。而肥胖和恶病质是相反的疾病重量谱的末端，这些病理具有一些潜在的扰动（例如线粒体功能障碍），当这些病变同时发生时可能会加剧功能降低。我们的实验室使新颖而重大的发现，肥胖的小鼠以瘦质量服用，无法在2-3个周期中生存化学治疗，5氟尿嘧啶（5FU）。确实，与所建议的相反，我们发现肥胖小鼠不受化学疗法诱导的恶病质的保护，并表现出恶化的骨骼肌毒性。线粒体的干扰是1）化学疗法引起的骨骼肌质量损失的核心，并且 2）已知存在肥胖和代谢功能障碍；但是，线粒体功能障碍和当这些病因共发生时，尚未评估结果功能缺陷。抗氧化剂已经存在显示可改善线粒体功能。确实，我们已经表明抗氧化剂饮食化合物，槲皮素可以减少癌症，癌症恶病质和化学疗法诱导的疲劳，并可以增加健康小鼠的线粒体功能。那就是槲皮素可能有望作为治疗的饮食策略与癌症及其疗法相关的病虫病在肥胖情况下。我提议的主要目标 F31是1）了解肥胖对5FU诱导的骨骼肌功能障碍的影响，2）机械和治疗见解旨在更好地提高肥胖症5FU的耐受性。我的中央假设是5FU诱导的线粒体损失和功能障碍被肥胖表型加剧介入与Quelletin将减轻5FU对骨骼肌的有害影响。测试这个假设，我提出了三个相关但独立的特定目的：1）检查肥胖对癌症的影响和5FU诱导的恶病质和功能损失； 2）确定线粒体在肥胖效果中的作用 5FU毒性； 3）探索饮食槲皮素在改善5FU治疗耐受性和外的效用目标毒性具有肥胖症。拟议的研究与我的培训目标保持一致，并将为我提供获得肥胖表型和天然化合物的专业知识的机会，作为治疗，线粒体健康与动态，卡希克西亚和功能测试。此外，专业发展培训将促进我研究独立道路的下一步。