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.

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.