Molecular Mechanisms of Age-related Muscle Loss

描述(由申请人提供)： 与年龄相关的骨骼肌萎缩，也被称为骨质疏松症，降低了许多退伍军人患者的健康和生活质量。然而，与年龄相关的肌肉萎缩的分子机制尚不清楚，也不存在药物治疗。因此，许多老年退伍军人遭受肌肉萎缩的后果，包括虚弱、摔倒、虚弱和丧失独立性。这给老年退伍军人、他们的家庭和整个社会带来了巨大的负担。我们的长期目标是了解与年龄相关的肌肉萎缩的分子机制，然后利用这些信息开发治疗方法。在之前的资助周期中，我们发现Gadd45a和p21是一种新的骨骼肌萎缩分子途径的关键介质。衰老以及其他导致肌肉萎缩的原因强烈地诱导人、小鼠和大鼠骨骼肌中Gadd45a mRNA的表达。这增加了Gadd45a蛋白的水平，进而增加了p21mRNA。结果，p21蛋白的水平上升，并触发了年龄相关性骨骼肌萎缩过程中发生的许多关键变化，包括蛋白质和线粒体的丢失，最终导致肌肉纤维萎缩。总而言之，这些结果强烈表明Gadd45a/p21通路在年龄相关性肌肉萎缩中起着关键作用。然而，这些数据也阐明了几个需要进一步研究的重要领域。例如，我们的数据表明，Gadd45a和p21的顺序诱导在骨骼肌萎缩中起着核心作用；但我们还不知道衰老如何增加骨骼肌Gadd45a的表达，或者Gadd45a如何增加p21的表达。此外，我们的数据表明，Gadd45a/p21通路是年龄相关性骨骼肌萎缩的潜在治疗靶点；但这一假设尚未得到验证。为了解决这些重要问题，我们提出了三个具体目标，都使用了老鼠模型。在目标1中，我们将检验两个转录因子(P53和ATF4)在骨骼肌衰老过程中导致Gadd45a mRNAs增加的假设。在目标2中，我们将检验两个Gadd45a相互作用蛋白(MEKK4和LRRC14)在Gadd45a介导的p21表达中发挥关键作用的假设。在目标3中，我们将验证这样的假设，即减少Gadd45a和/或p21可以恢复衰老萎缩肌肉中骨骼肌线粒体和肌肉纤维的大小。通过这些研究，我们希望阐明年龄相关性肌肉萎缩的基本分子机制和新的治疗方法，这是一种影响许多退伍军人的致残性疾病。

DESCRIPTION (provided by applicant): Age-related skeletal muscle atrophy, also known as sarcopenia, diminishes the health and quality of life of many Veteran patients. However, the molecular mechanisms of age-related muscle atrophy are poorly understood, and a pharmacologic therapy does not exist. As a result, many elderly Veterans suffer the consequences of muscle atrophy, including weakness, falls, debilitation, and loss of independence. This places enormous burdens on elderly Veterans, their families, and society in general. Our long-term goal is to understand molecular mechanisms of age-related muscle atrophy, and then use that information to develop a therapy. In the previous grant cycle, we discovered Gadd45a and p21 as critical mediators of a novel molecular pathway to skeletal muscle atrophy. Aging, as well as other causes of muscle atrophy, strongly induce Gadd45a mRNA in skeletal muscle of humans, mice and rats. This increases the level of Gadd45a protein, which in turn increases p21 mRNA. As a result, the level of p21 protein rises and triggers many of the critical changes that occur during age-related skeletal muscle atrophy, including loss of protein and mitochondria, and ultimately, muscle fiber atrophy. Collectively, these results strongly suggest a key role for the Gadd45a/p21 pathway in age-related muscle atrophy. However, these data also elucidate several important areas for further investigation. For example, our data indicate that the sequential induction of Gadd45a and p21 plays a central role in skeletal muscle atrophy; but we do not yet know how aging increases skeletal muscle Gadd45a expression, or how Gadd45a increases p21 expression. In addition, our data suggest the Gadd45a/p21 pathway as a potential therapeutic target in age-related skeletal muscle atrophy; but this hypothesis has not yet been tested. To resolve these important issues, we propose three specific aims, all using mouse models. In Aim 1, we will test the hypothesis that two transcription factors (p53 and ATF4) are responsible for increasing Gadd45a mRNAs during skeletal muscle aging. In Aim 2, we will test the hypothesis that two Gadd45a-interacting proteins (MEKK4 and LRRC14) play key roles in Gadd45a-mediated p21 expression. In Aim 3, we will test the hypothesis that reducing Gadd45a and/or p21 permits recovery of skeletal muscle mitochondria and muscle fiber size in aged, atrophic muscle. Through these studies, we hope to elucidate fundamental molecular mechanisms and new therapeutic approaches for age-related muscle atrophy, a disabling condition that affects many Veteran patients.