Dietary fats, mitochondrial function and muscle health in cancer patients

癌症患者的膳食脂肪、线粒体功能和肌肉健康

• 批准号: 9456294
• 负责人: MARTHA A BELURY
• 金额: $ 19.97万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9456294
• 关键词: ATP Synthesis Pathway; Activities of Daily Living; Adjuvant; Adjuvant Therapy; Adverse effects; Affect; Anthracyclines; Attenuated; Automobile Driving; Binding; Biological Assay; Biological Markers; Breast; Breast Cancer Patient; Breast Cancer survivor; Cancer Patient; Cardiac; Cardiac Edema; Cardiolipins; Cardiomyopathies; Cellular Structures; Cessation of life; Clinical assessments; Coupling; Data; Diagnosis; Diet; Dietary Fats; Early Diagnosis; Early treatment; Electron Transport; Environment; Event; Exhibits; Face; Goals; Health; Heart failure; Inner mitochondrial membrane; Knowledge; Link; Linoleic Acids; Lipids; Magnetic Resonance; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Mass in breast; Measurement; Measures; Mediating; Methods; Mitochondria; Morbidity - disease rate; Muscle; Muscle Cells; Muscle Mitochondria; Muscle Weakness; Muscle function; Muscular Atrophy; Myocardial dysfunction; Myocardium; Oxidative Phosphorylation; Patients; Peripheral Blood Lymphocyte; Phospholipids; Phosphorus; Prevention strategy; Production; Prospective Studies; Proteins; Rattus; Research Proposals; Skeletal Muscle; Structure; Survival Rate; Survivors; Symptoms; Techniques; Thinness; Topoisomerase; Toxic effect; Woman; Work; adverse outcome; base; breast cancer diagnosis; cancer recurrence; chemotherapy; diagnostic biomarker; essential phospholipids; experience; functional decline; heart function; improved; innovation; malignant breast neoplasm; mortality; muscle form; muscle physiology; novel; premature; prevent; prospective; reduced muscle mass; skeletal; spectroscopic imaging; therapeutic development; therapy design

Thanks to early detection and treatment, women can expect excellent survival after an initial diagnosis of breast cancer. However, widely-used treatments such as anthracycline chemotherapy (AC) incur significant morbidity and mortality via effects on skeletal and cardiac muscle. Cardiomyopathy affects 1 in 5 breast cancer survivors within 3 years of diagnosis and over half of breast cancer survivors develop symptoms attributable to skeletal muscle weakness. A key mechanism underlying these toxicities involves adverse effects in mitochondria on cardiolipin, an essential phospholipid that forms the inner mitochondrial membrane and supports ATP synthesis. Anthracyclines (AC) in particular bind cardiolipin, rendering it unavailable to support proteins involved with the electron transport chain. Disturbing mitochondrial cardiolipin reduces ATP production in both skeletal and cardiac muscle. However, there has been no study to date in breast cancer patients showing that decreased cardiolipin levels are associated with the decline of structure and function of skeletal and cardiac muscle also diminishes from chemotherapy treatment. Our team has generated ground-breaking preliminary data in breast cancer survivors showing that cardiolipin levels, via a novel and robust assay in peripheral blood lymphocytes, predict reduced muscle mass in breast cancer survivors. We have also implemented direct measurement of cardiac function and structure using cardiac magnetic resonance (CMR) imaging and assessment of mitochondrial function in skeletal muscle using the well-established technique of 31-phosphorus magnetic resonance spectroscopy (31P-MRS). We recently completed a prospective study using cardiac strain measurement, a highly sensitive magnetic resonance-based biomarker of subclinical cardiac dysfunction, showing early decline in LV strain after anthracycline chemotherapy in breast cancer patients. We also have the ability to analyze cardiolipin profiles and lipids important to cardiolipin function. We are now poised to conduct an essential study of skeletal and cardiac muscle integrated with careful clinical assessment in breast cancer survivors receiving AC towards a long-term goal of targeting cardiolipin to reduce morbidity and mortality. Aim 1: Measure the relationships among skeletal muscle, cardiac muscle and cardiolipin status in breast cancer survivors. Aim 2: Assess longitudinal chemotherapy-induced changes in cardiolipin composition, skeletal muscle and cardiac muscle.

由于早期发现和治疗，女性在初步诊断后可以期望获得良好的生存率 乳腺癌。然而，广泛使用的治疗方法，例如蒽环类化疗（AC），会导致 通过对骨骼和心肌的影响而导致显着的发病率和死亡率。心肌病影响 1 人 诊断后 3 年内有 5 名乳腺癌幸存者，其中超过一半的乳腺癌幸存者发展为乳腺癌 骨骼肌无力引起的症状。这些毒性的关键机制 涉及线粒体对心磷脂的不利影响，心磷脂是形成内部的必需磷脂。 线粒体膜并支持 ATP 合成。蒽环类药物 (AC) 特别结合心磷脂， 使其无法支持电子传递链中涉及的蛋白质。令人不安的 线粒体心磷脂减少骨骼肌和心肌中 ATP 的产生。然而，有 迄今为止，还没有针对乳腺癌患者的研究表明心磷脂水平降低 与骨骼和心肌的结构和功能下降相关的能量也从 化疗治疗。我们的团队已经生成了乳腺癌的突破性初步数据 幸存者通过外周血淋巴细胞中的一种新颖而可靠的检测表明心磷脂水平， 预测乳腺癌幸存者的肌肉质量减少。我们还实施了直接测量 使用心脏磁共振（CMR）成像和评估心脏功能和结构 使用成熟的 31-磷磁技术研究骨骼肌中的线粒体功能 共振光谱（31P-MRS）。我们最近完成了一项使用心脏应变的前瞻性研究 测量，一种基于磁共振的高度灵敏的亚临床心脏功能障碍生物标志物， 显示乳腺癌患者接受蒽环类化疗后左室应变早期下降。我们也 能够分析对心磷脂功能重要的心磷脂谱和脂质。我们现在 准备对骨骼和心肌进行一项重要的研究，并结合仔细的临床 对接受 AC 的乳腺癌幸存者进行评估，以实现以心磷脂为目标的长期目标 降低发病率和死亡率。目标 1：测量骨骼肌、心肌之间的关系 和乳腺癌幸存者的心磷脂状态。目标 2：评估纵向化疗引起的 心磷脂成分、骨骼肌和心肌的变化。