Prevention and Treatment of Skeletal Muscle Atrophy

描述(由申请人提供)： 骨骼肌萎缩代表着退伍军人患者巨大的未得到满足的医疗需求。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、慢性阻塞性肺疾病、糖尿病、中风、肾功能衰竭、危重疾病和脊髓损伤。骨骼肌萎缩的影响包括虚弱、活动减少、跌倒、骨折、虚弱、长期住院和康复、疗养院安置，以及死亡率增加。虽然骨骼肌萎缩在退伍军人中具有广泛的临床影响，但目前还不存在针对肌肉萎缩的药物疗法，而且目前的治疗方法(营养和身体康复)往往无效和/或不可行。我们的长期目标是开发一种治疗骨骼肌萎缩的药物疗法。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，然后将这些特征结合一种新的药物发现方法来确定两个小分子(熊果酸和化合物A)作为预测的人类骨骼肌萎缩的药物抑制剂。在小鼠模型上，我们发现熊果酸和化合物A可以预防和逆转骨骼肌萎缩，增加肌肉力量，提高运动能力。除了在小鼠身上的这些作用外，我们还发现熊果酸和化合物A促进了人骨骼肌管的生长，这是一种人类骨骼肌的体外模型。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，这表明有很好的潜力转化为资深患者。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，但一些关键问题仍然没有答案。例如，我们还不知道熊果酸和化合物A是如何减少肌肉萎缩和改善肌肉功能的。此外，熊果酸和化合物A在结构上不同，在生理生化作用上也表现出一定的差异，这表明熊果酸和化合物A联合使用可能比单独使用任何一种化合物更有益。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。由于骨骼肌的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，我们将检验乌索酸和化合物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、刺激合成信号的假说。总而言之，这些研究将为乌索酸和化合物A治疗骨骼肌萎缩患者的临床研究提供重要的机制基础。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联合使用是否比单独使用任何一种化合物更有益。我们将验证乌索酸和化合物A的组合比单独使用任何一种化合物更能预防和逆转骨骼肌萎缩、增加力量和提高运动能力的假设。如果熊果酸和化合物A的联合治疗在肌肉萎缩方面显示出额外的益处，联合治疗将被推进到临床研究中。通过这些研究，我们希望开发新的治疗药物来治疗骨骼肌萎缩，并提高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，它损害了健康

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