Prevention and Treatment of Skeletal Muscle Atrophy

骨骼肌萎缩的预防和治疗

• 批准号: 9391612
• 负责人: Christopher M Adams
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-10-01 至 2018-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9391612
• 关键词: Affect; Bed rest; Biochemical; Cell Respiration; Chemicals; Chronic Obstructive Airway Disease; Clinical; Clinical Research; Combined Modality Therapy; Critical Illness; Data; Diabetes Mellitus; Elderly; Equilibrium; Exercise; Exhibits; Family; Food; Foundations; Fracture; Gene Expression Profile; Goals; Growth; Health; Heart failure; Hospitalization; Human; Immobilization; Independent Living; Injury; Insulin-Like Growth Factor I; Kidney Failure; Lead; Limb structure; Link; Malignant Neoplasms; Medical; Medicine; Methods; Mitochondria; Mus; Muscle Fibers; Muscle Proteins; Muscle function; Muscular Atrophy; Nursing Homes; Orthopedics; Patients; Pharmacology; Physical Rehabilitation; Physiological; Population; Prevention; Protein Biosynthesis; Proteins; Public Health; Quality of life; Recovery; Rehabilitation Nursing; Rehabilitation therapy; Research; Respiration; Safety; Signal Pathway; Signal Transduction; Skeletal Muscle; Spinal Cord; Spinal cord injury; Stroke; Testing; Therapeutic; Therapeutic Agents; Translations; Veterans; Work; age related; base; drug discovery; exercise capacity; falls; human subject; improved; in vitro Model; in vivo; inhibitor/antagonist; mRNA Expression; mortality; mouse model; muscle form; muscle strength; novel therapeutics; nutrition; prevent; protein degradation; public health relevance; skeletal; skeletal muscle wasting; small molecule; small molecule inhibitor; ursolic acid; young adult

DESCRIPTION (provided by applicant): Skeletal muscle atrophy represents an enormous unmet medical need in Veteran patients. Frequent causes of skeletal muscle atrophy include orthopedic injuries, bed rest, advanced age, cancer, heart failure, COPD, diabetes, stroke, renal failure, critical illness and spinal cord injuy. Effects of skeletal muscle atrophy include weakness, reduced activity, falls, fractures, debilitation, prolonged hospitalization and rehabilitation, nursing home placement, and increased mortality. Although skeletal muscle atrophy has broad clinical impact in the Veteran population, a pharmacologic therapy for muscle atrophy does not exist, and current therapeutic approaches (nutrition and physical rehabilitation) are often ineffective and/or unfeasible. Our long-term goal is to develop a pharmacologic therapy for skeletal muscle atrophy. In preliminary studies, we studied human subjects to determine mRNA expression signatures of human skeletal muscle atrophy, and then used these signatures in conjunction with a novel drug discovery method to identify two small molecules (ursolic acid and compound A) as predicted pharmacologic inhibitors of human skeletal muscle atrophy. Using mouse models, we found that ursolic acid and compound A prevent and reverse skeletal muscle atrophy, increase muscle strength, and improve exercise capacity. In addition to these effects in mice, we found that ursolic acid and compound A stimulate growth of human skeletal myotubes, an in vitro model of human skeletal muscle. Importantly, data from us and others suggest that ursolic acid and compound A have favorable safety profiles, suggesting good potential for translation to Veteran patients. Although these data identify ursolic acid and compound A as exciting potential therapeutic agents to prevent and reverse skeletal muscle atrophy in Veteran patients, some critical questions remain unanswered. For example, we do not yet understand how ursolic acid and compound A reduce muscle atrophy and improve muscle function. In addition, ursolic acid and compound A are structurally dissimilar and exhibit some differences in their physiological and biochemical effects, suggesting that the combination of ursolic acid and compound A could be more beneficial than either compound alone. To determine mechanisms of action and potential for combination therapy, we propose two aims. In Specific Aim 1, we will use human skeletal myotubes to determine cellular mechanisms that ursolic acid and compound A utilize to increase muscle mass and improve muscle function. Since skeletal muscle mass and function are tightly linked to skeletal muscle protein, mitochondria and anabolic signaling, we will test th hypotheses that ursolic acid and compound A increase the net balance of protein synthesis to protein degradation, increase mitochondrial mass and respiration, and stimulate anabolic signaling. Collectively, these studies will provide an important mechanistic foundation for clinica studies of ursolic acid and compound A in patients with skeletal muscle atrophy. In Specific Aim 2, we will use mouse models to determine if the combination of ursolic acid and compound A is more beneficial than either compound alone. We will test the hypotheses that the combination of ursolic acid and compound A prevents and reverses skeletal muscle atrophy, increases strength, and improves exercise capacity more than either compound alone. If the combination of ursolic acid and compound A demonstrates additional benefit in muscle atrophy, combination therapy would be carried forward to clinical studies. Through these studies, we hope to develop new therapeutic agents for skeletal muscle atrophy, and quality of life of many Veteran patients. a common and debilitating condition that diminishes the health

描述（由申请人提供）： 骨骼肌萎缩代表了退伍军人患者巨大的未满足的医疗需求。骨骼肌萎缩的常见原因包括骨科损伤、卧床休息、高龄、癌症、心力衰竭、COPD、糖尿病、中风、肾衰竭、危重病和脊髓损伤。骨骼肌萎缩的影响包括虚弱、活动减少、福尔斯、骨折、虚弱、住院和康复时间延长、疗养院安置和死亡率增加。虽然骨骼肌萎缩在退伍军人人群中具有广泛的临床影响，但肌肉萎缩的药物治疗并不存在，并且目前的治疗方法（营养和物理康复）通常无效和/或不可行。我们的长期目标是开发骨骼肌萎缩的药物治疗。在初步研究中，我们研究了人类受试者，以确定人类骨骼肌萎缩的mRNA表达特征，然后使用这些特征结合一种新的药物发现方法，以确定两种小分子（熊果酸和化合物A）作为人类骨骼肌萎缩的预测药理学抑制剂。使用小鼠模型，我们发现熊果酸和化合物A预防和逆转骨骼肌萎缩，增加肌肉力量，提高运动能力。除了在小鼠中的这些作用之外，我们发现熊果酸和化合物A刺激人骨骼肌管（人骨骼肌的体外模型）的生长。重要的是，来自我们和其他人的数据表明，熊果酸和化合物A具有良好的安全性，这表明它具有很好的转化为退伍军人患者的潜力。尽管这些数据确定熊果酸和化合物A是预防和逆转退伍军人患者骨骼肌萎缩的令人兴奋的潜在治疗剂，但一些关键问题仍未得到解答。例如，我们还不了解熊果酸和化合物A如何减少肌肉萎缩和改善肌肉功能。此外，熊果酸和化合物A在结构上不同，并且在它们的生理和生化作用方面表现出一些差异，这表明熊果酸和化合物A的组合可能比单独的任一种化合物更有益。为了确定联合治疗的作用机制和潜力，我们提出了两个目标。在具体目标1中，我们将使用人骨骼肌管来确定熊果酸和化合物A用于增加肌肉质量和改善肌肉功能的细胞机制。由于骨骼肌质量和功能与骨骼肌蛋白质、线粒体和合成代谢信号密切相关，我们将测试熊果酸和化合物A增加蛋白质合成与蛋白质降解的净平衡、增加线粒体质量和呼吸并刺激合成代谢信号的假设。这些研究为熊果酸和复方A治疗骨骼肌萎缩的临床研究提供了重要的机制基础。在具体目标2中，我们将使用小鼠模型来确定熊果酸和化合物A的组合是否比单独使用任何一种化合物更有益。我们将测试熊果酸和化合物A的组合预防和逆转骨骼肌萎缩，增加力量，并提高运动能力比单独使用任何一种化合物的假设。如果熊果酸和化合物A的组合在肌肉萎缩中表现出额外的益处，则组合疗法将进行临床研究。通过这些研究，我们希望开发新的治疗骨骼肌萎缩的药物，并改善许多退伍军人患者的生活质量。一种常见的使人衰弱的疾病，