Molecular pathogenesis of skeletal muscle atrophy

项目摘要/摘要 与年龄相关的骨骼肌无力和萎缩会降低许多老年人的健康和生活质量 人民。然而，在衰老过程中导致肌肉无力和萎缩的分子机制是 人们对此知之甚少，也不存在非常有效的治疗方法。因此，许多老年人 个人遭受肌肉萎缩的后果，包括虚弱、疲劳、活动受限、摔倒、 虚弱和丧失独立性。这些问题给患者、他们的家人和 一般的社会。我们的研究重点是骨骼肌萎缩的分子机制和 小分子的发现和发展可能用于预防或治疗这种疾病的小分子 条件。在对小鼠模型进行的初步研究中，我们确定了第一个蛋白质的例子，这种蛋白质 是骨骼肌质量、质量、力量和耐力运动能力的丧失所必需的 衰老：转录因子ATF4。我们发现缺乏ATF4表达的条件性基因敲除小鼠 骨骼肌纤维从出生时就正常发育，并显示出正常的肌肉质量和功能到中部 年龄；然而，它们抵抗年龄导致的肌肉质量、力量、质量和耐力的下降。 锻炼能力。相反，ATF4在年轻成人骨骼肌纤维中的强制表达足以 导致萎缩。此外，我们发现了两个结构不同的小分子，它们显著 减少与年龄相关的肌肉无力和萎缩，有趣的是，这两个小分子都能钝化ATF4 老年骨骼肌的活动。综上所述，这些结果强烈表明ATF4通路在 与年龄相关的肌肉无力和萎缩。此外，这些数据阐明了进一步研究的几个重要领域 调查。例如，我们还不知道ATF4活性的特定降低是否适用于老年人 骨骼肌，足以治疗与年龄相关的肌肉无力和萎缩。而且，下游 ATF4在衰老过程中促进肌肉无力和萎缩的机制尚不清楚。至 为了开始解决这些重要的问题，我们提出了三个具体的目标，都使用了老鼠模型。在目标1中，我们 将检验这样一种假设，即急性、有针对性地降低老年人骨骼肌纤维中ATF4的表达 小鼠将逆转与年龄相关的肌肉质量和功能变化。在目标2中，我们将确定ATF4依赖 年龄相关性骨骼肌萎缩所需的mRNAs，测试ATF4促进 通过激活某些骨骼肌基因造成的肌肉损失，这些基因的蛋白质产物是肌肉纤维所必需的 衰老过程中的萎缩。在目标3中，我们将确定ATF4在老年骨骼蛋白质代谢中的作用 肌肉，测试ATF4至少部分导致与年龄相关的蛋白质排列紊乱的假设 导致肌肉无力和萎缩的新陈代谢。通过这些研究，我们希望能够澄清 老年性肌无力的基本分子机制和新的治疗方法 萎缩症是一种致残疾病，仅在美国就影响了数百万老年人。

PROJECT SUMMARY / ABSTRACT Age-related skeletal muscle weakness and atrophy diminish the health and quality of life of many elderly people. However, the molecular mechanisms that cause muscle weakness and atrophy during aging are poorly understood, and highly effective therapeutic approaches do not exist. As a result, many elderly individuals suffer the consequences of muscle atrophy, including weakness, fatigue, restricted activity, falls, debilitation, and loss of independence. These issues place enormous burdens on patients, their families, and society in general. Our research program is focused on molecular mechanisms of skeletal muscle atrophy and the discovery and development of small molecules that could potentially be used to prevent or treat this condition. In preliminary studies, performed in mouse models, we identified the first example of a protein that is required for the loss of skeletal muscle mass, quality, strength, and endurance exercise capacity during aging: the transcription factor ATF4. We found that conditional knockout mice lacking ATF4 expression in skeletal muscle fibers from birth develop normally and exhibit normal muscle mass and function into middle age; however, they are resistant to age-induced declines in muscle mass, strength, quality, and endurance exercise capacity. Conversely, forced expression of ATF4 in young adult skeletal muscle fibers is sufficient to induce atrophy. Furthermore, we discovered two structurally dissimilar small molecules that significantly reduce age-related muscle weakness and atrophy, and interestingly, both of these small molecules blunt ATF4 activity in aged skeletal muscle. Collectively, these results strongly suggest a key role for the ATF4 pathway in age-related muscle weakness and atrophy. Moreover, these data elucidate several important areas for further investigation. For example, we do not yet know if a specific reduction of ATF4 activity, acutely applied to aged skeletal muscle, is sufficient to treat age-related muscle weakness and atrophy. Moreover, the downstream mechanisms by which ATF4 promotes muscle weakness and atrophy during aging are not understood. To begin to resolve these important issues, we propose three specific aims, all using mouse models. In Aim 1, we will test the hypothesis that an acute, targeted reduction of ATF4 expression in skeletal muscle fibers of old mice will reverse age-related changes in muscle mass and function. In Aim 2, we will identify ATF4-dependent mRNAs that are required for age-related skeletal muscle atrophy, testing the hypothesis that ATF4 promotes muscle loss by activating certain skeletal muscle genes whose protein products are necessary for muscle fiber atrophy during aging. In Aim 3, we will determine the role of ATF4 in protein metabolism in aged skeletal muscle, testing the hypothesis that ATF4 is at least partly responsible for age-related derangements in protein metabolism that are central to muscle weakness and atrophy. Through these studies, we hope to elucidate fundamental molecular mechanisms and new therapeutic approaches for age-related muscle weakness and atrophy, a disabling condition that affects millions of elderly people in the US alone.