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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.

项目总结/文摘