Impact of obesity on chemotherapy-induced muscle mitochondrial dysfunction

项目总结 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 在他们的一生中。然而，关于体重状况对癌症患者生活的影响的文献很少。 整个治疗过程中的质量和功能能力。例如，我们对肥胖影响的了解 癌症和化疗引起的恶病质--无意中瘦体重的减少，这直接导致了 功能依赖、治疗结果差、存活率下降--是不完整的。“肥胖” “悖论”已被假定；然而，流行病学对艾滋病的益处/危害仍然模棱两可。 治疗前体重和体重指数较高。而肥胖和恶病质是相反的疾病 在体重谱的两端，这些病理都有一些潜在的扰动(例如线粒体 功能障碍)，当这些疾病同时发生时，可能会加剧功能减退。我们的实验室制作了 一项新的重大发现是，肥胖小鼠在服用瘦身药物后，无法存活2-3个周期 化疗，5-氟尿嘧啶(5FU)。事实上，与所建议的相反，我们发现 肥胖小鼠对化疗引起的恶病质没有保护作用，并表现出骨骼肌恶化 毒物。线粒体的破坏是1)化疗导致的骨骼肌质量下降的核心，以及 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，由此产生的功能缺陷还没有得到评估。抗氧化剂一直是 显示能改善线粒体功能。事实上，我们已经证明了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 健康小鼠的线粒体功能。因此，作为一种饮食治疗策略，槲皮素可能大有可为 与癌症相关的恶病质及其在肥胖条件下的治疗。我提议的主要目标是 F31是为了1)了解肥胖对5FU诱导的骨骼肌功能障碍的影响，以及2)提供 旨在更好地改善肥胖患者对5FU耐受性的机械性和治疗性见解。我的中央 假说是5FU诱导的线粒体丢失和功能障碍随着肥胖表型的加剧而加剧 用槲皮素进行干预将减轻5FU对骨骼肌的有害影响。为了测试这一点 假设，我提出了三个相关但独立的具体目标：1)研究肥胖对癌症的影响 和5FU诱导的恶病质和功能丧失；2)确定线粒体在肥胖加重中的作用 3)探讨膳食中的槲皮素对提高5FU治疗耐受性和非耐受性的作用。 以肥胖为目标的毒性。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学、线粒体的专业知识 健康和动力、恶病质和功能测试。此外，职业发展培训将 推动我在研究独立道路上的下一步。

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.