The Role of AMPK in Regulating Muscle Mass and Function in Cancer Cachexia

AMPK 在调节癌症恶病质的肌肉质量和功能中的作用

基本信息

批准号：
10661299
负责人：
Haiming Liu Kerr
金额：
$ 12.21万
依托单位：
UNIVERSITY OF WASHINGTON
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：
2023-06-01 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10661299
关键词：
Adenosine Monophosphate Adult Affect Agonist Animals Anorexia Antiinflammatory Effect Attenuated Autophagocytosis Biogenesis Body Composition Body Weight Body Weight decreased Cachexia Cancer Etiology Cancer Model Cancer Patient Cisplatin Coculture Techniques Colon Carcinoma Complex Desire for food Development Drug usage Eating FDA approved Fasting Fatigue Fatty acid glycerol esters Fiber Functional disorder Genetic Goals Head and Neck Cancer Hydrogen Peroxide Impairment Implant In Vitro Inflammation Inflammatory Interleukin-1 beta Interleukin-6 Intervention Investigation Kinetics Lewis Lung Carcinoma Lewis lung carcinoma cell Longevity Lung MAP Kinase Gene Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of ovary Malignant neoplasm of testis Malignant neoplasm of urinary bladder Measurement Measures Mediating Medical Care Costs Metabolism Mitochondria Modeling Modification Molecular Mus Muscle Muscle Fibers Muscle Weakness Muscle function Muscular Atrophy Muscular Dystrophies Myopathy NF-kappa B Neuromuscular Junction Outcome Oxidative Stress Palpable Pathologic Pathway interactions Patients Physical Function Platinum Play Production Protein Kinase Quality of life Reactive Oxygen Species Regulation Relaxation Reporting Research Research Design Research Personnel Respiration Ribonucleotides Rodent Model Role SIRT1 gene Signal Pathway Signal Transduction Skeletal Muscle Small Interfering RNA Spectrum Analysis Stains Syndrome TNF gene Testing Therapeutic Transgenic Mice Treadmill Tests Wasting Syndrome Wild Type Mouse cancer cachexia cancer therapy cancer type cell type chemotherapeutic agent chemotherapy cytokine experimental study grasp improved in vivo interest mitochondrial dysfunction muscle form muscle physiology novel novel therapeutics pharmacologic prevent protein kinase inhibitor protein kinase modulator response sensor side effect therapeutic target tumor

项目摘要

PROJECT SUMMARY/ABSTRACT Cancer cachexia (CC) is a wasting syndrome characterized by decreased appetite, weight loss, and muscle wasting in cancer patients leading to decreased physical function and poor quality of life, shortened lifespan, and higher medical costs. To this date, there is no approved treatment for CC. Paradoxically, muscle wasting and weakness are also very common side effects of some chemotherapeutic agents such as cisplatin, a first-line therapy for several cancer types. Since current interventions for preventing or treating cachexia associated with cancer or cisplatin are suboptimal, there is an urgent need to develop new therapies to improve muscle mass and function in these conditions. 5’-adenosine monophosphate-activated protein kinase (AMPK) is an intracellular energy sensor that plays a central role in skeletal muscle physiology through the regulation of mitochondrial biogenesis and metabolism. It has also been shown to decrease inflammation in a variety of cell types. AMPK is of particular interest in the context of CC because, although the mechanisms underlying cancer cachexia are not fully understood, one of the primary triggers of CC is increased inflammation and oxidative stress. Impaired mitochondrial function is also thought to be one of the main contributors to muscle dysfunction in CC. However, the function of AMPK in CC, as well as its potential therapeutic role in preventing muscle wasting and weakness are not known. This study aims to characterize the role of AMPK in cisplatin- and lung cancer tumor (Lewis Lung Carcinoma, LLC)- induced CC, and evaluate the potential for modulating AMPK as a therapeutic target for these conditions. Specific Aim 1A will investigate if genetic (AMPKα2 activity inhibited) or pharmacological inhibition of AMPK (Compound C) exacerbates cisplatin-induced muscle wasting and dysfunction in mice; whereas promoting AMPK activation by its agonist AICAR attenuates this myopathy. Specific Aim 1B will determine whether activating AMPK attenuates cisplatin-induced myopathy in C2C12 myotubes and characterize the signaling pathways involved. Specific Aim 2A will determine if AICAR attenuates LLC tumor-induced muscle wasting and dysfunction and Compound C exacerbates these deficits, and Specific Aim 2B will determine the same effects of AMPK modification on LLC media-cocultured C2C12 myotubes and elucidate the underlying molecular pathways. The overall hypothesis is that AMPK is essential for maintaining muscle function during cachexia; promoting AMPK activation by AICAR counteracts cisplatin- or tumor-induced muscle wasting and weakness, whereas inhibiting AMPK activation will exacerbate this myopathy. We postulate that the effects of AMPK are mediated by suppressing inflammation and oxidative stress while promoting mitochondrial function. Ultimately, our findings from this study will provide evidence of the potential therapeutic role of AMPK in CC, and benefit cancer patients by improving their quality of life and longevity. This project will also allow me to transit to an independent investigator in cancer cachexia and muscle research.

项目概要/摘要癌症恶病质 (CC) 是一种消耗综合征，其特征是食欲下降、体重减轻和肌肉萎缩癌症患者的消瘦导致身体机能下降、生活质量差、寿命缩短矛盾的是，迄今为止，还没有批准的治疗肌肉萎缩和肌肉萎缩的方法。无力也是一些化疗药物（例如一线化疗药物顺铂）非常常见的副作用。自从目前用于预防或治疗与恶病质相关的干预措施以来，对几种癌症类型的治疗。癌症或顺铂效果不佳，迫切需要开发新疗法来改善肌肉质量并在这些条件下发挥作用。 5’-单磷酸腺苷激活蛋白激酶 (AMPK) 是一种细胞内能量传感器，在通过调节线粒体生物发生和代谢在骨骼肌生理学中发挥核心作用。 AMPK 也被证明可以减少多种细胞类型的炎症。 CC 的背景，因为尽管癌症恶病质的机制尚未完全了解，但其中之一 CC 的主要诱因是炎症增加和氧化应激受损。也被认为是 CC 中肌肉功能障碍的主要原因之一。在 CC 中，以及它在预防肌肉萎缩和无力方面的潜在治疗作用尚不清楚。研究旨在表征 AMPK 在顺铂和肺癌肿瘤中的作用 (Lewis Lung Carcinoma, LLC)- 诱导 CC，并评估调节 AMPK 作为这些疾病的治疗靶点的潜力。具体目标 1A 将研究 AMPK 是否受到遗传（AMPKα2 活性抑制）或药理学抑制 (化合物C)恶化顺铂引起的小鼠肌肉萎缩和功能障碍； AMPK 的激动剂 AICAR 激活可减轻这种肌病，具体目标 1B 将确定是否如此。激活 AMPK 可减轻顺铂诱导的 C2C12 肌管肌病并表征信号传导具体目标 2A 将确定 AICAR 是否能减轻 LLC 肿瘤引起的肌肉萎缩和功能障碍和化合物 C 会使这些缺陷恶化，而特定目标 2B 将确定相同的效果 AMPK 修饰对 LLC 培养基共培养的 C2C12 肌管的影响并阐明了潜在的分子总体假设是 AMPK 对于恶病质期间的肌肉维持功能至关重要。 AICAR 促进 AMPK 激活可以抵消顺铂或肿瘤引起的肌肉萎缩和无力，而抑制 AMPK 激活会使这种肌病恶化。我们假设 AMPK 的作用是。最终通过抑制炎症和氧化应激同时促进线粒体功能来介导。我们的研究结果将为 AMPK 在 CC 中的潜在治疗作用提供证据，并有益于通过提高癌症患者的生活质量和寿命，这个项目也将使我能够过渡到一个新的阶段。癌症恶病质和肌肉研究的独立研究者。