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

• 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
• 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

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.

项目概要 肥胖会增加患癌症的风险；因此，肥胖的人更有可能接受化疗。 然而，关于体重状况对癌症患者生活影响的文献却很少。 例如，我们对肥胖影响的了解。 癌症和化疗引起的恶病质 - 瘦体重的无意损失，直接导致 功能依赖性、治疗结果不佳和生存率下降——这是不完整的。 悖论”已被假设；然而，流行病学对于这种现象的好处/坏处仍然模棱两可。 治疗前体重和体重指数高，而肥胖和恶病质是相反的疾病。 在权重谱的末端，这些病理学共享一些潜在的扰动（例如线粒体 当这些疾病同时发生时，可能会加剧功能下降。 新颖而重大的发现是，给予瘦体重的肥胖小鼠无法存活 2-3 个周期 化疗药物 5 氟尿嘧啶 (5FU) 事实上，与所建议的相反，我们发现了这一点。 肥胖小鼠无法抵抗化疗引起的恶病质，并且骨骼肌恶化 线粒体破坏是 1) 化疗引起的骨骼肌质量损失的核心； 2) 已知存在肥胖和代谢功能障碍；然而，线粒体功能障碍和 当这些疾病同时发生时，尚未评估由此产生的功能缺陷。 事实上，我们已经证明抗氧化剂饮食化合物， 槲皮素，可以减少癌症、癌症恶病质和化疗引起的疲劳，并可以增加 因此，槲皮素有望作为一种治疗饮食策略。 我提出的主要目标是与癌症相关的恶病质及其在肥胖情况下的治疗。 F31 旨在 1) 了解肥胖对 5FU 引起的骨骼肌功能障碍的影响，以及 2) 提供 旨在更好地改善 5FU 肥胖耐受性的机制和治疗见解。 假设是 5FU 诱导的线粒体丢失和功能障碍会因肥胖表型而加剧 使用槲皮素进行干预将减轻 5FU 对骨骼肌的有害影响。 假设，我提出三个相关但独立的具体目标：1）检查肥胖对癌症的影响 和5FU引起的恶病质和功能丧失；2)确定线粒体在肥胖加剧中的作用； 5FU 毒性；3) 探索膳食槲皮素在改善 5FU 治疗耐受性和副作用方面的效用 拟议的研究与我的培训目标一致，并将为我提供 有机会获得肥胖表型和天然化合物作为治疗、线粒体方面的专业知识 此外，还将提供健康和动态、恶病质和功能测试。 促进我在独立研究的道路上迈向下一步。