Molecular pathogenesis of skeletal muscle atrophy

骨骼肌萎缩的分子发病机制

• 批准号: 10188425
• 负责人: Christopher M Adams
• 金额: $ 47.21万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-22 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10188425
• 关键词: Acute; Affect; Age; Aging; Area; Atrophic; Biochemical; Biology; Birth; Cell physiology; Data; Development; Elderly; Exhibits; Family; Fatigue; Gene Expression; Genes; Health; Impairment; Individual; Investigation; Knock-out; Knockout Mice; Lead; Light; Mediator of activation protein; Medical; Messenger RNA; Molecular; Mus; Muscle; Muscle Fibers; Muscle Proteins; Muscle Weakness; Muscle function; Muscular Atrophy; Myopathy; Pathogenesis; Pathway interactions; Patients; Protein Biosynthesis; Proteins; Proteomics; Quality of life; RNA Interference; Regulation; Research; Resistance; Role; Skeletal Muscle; Societies; Structure; System; Testing; Transcript; Ubiquitin; Wild Type Mouse; Work; age related; age-related muscle loss; age-related muscle weakness; aged; base; conditional knockout; endurance exercise; exercise capacity; falls; in vivo; innovation; middle age; mouse model; multicatalytic endopeptidase complex; muscle aging; muscle form; novel therapeutic intervention; prevent; programs; protein metabolism; skeletal muscle metabolism; skeletal muscle wasting; skeletal muscle weakness; small molecule; therapeutic target; therapeutically effective; transcription factor; treatment strategy; young adult

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.

项目概要/摘要 与年龄相关的骨骼肌无力和萎缩降低了许多老年人的健康和生活质量 人们。然而，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，且不存在高效的治疗方法。结果，很多老人 个体遭受肌肉萎缩的后果，包括虚弱、疲劳、活动受限、跌倒、 身体虚弱，失去独立性。这些问题给患者及其家属带来了巨大的负担 整个社会。我们的研究项目专注于骨骼肌萎缩的分子机制和 发现和开发可能用于预防或治疗这种疾病的小分子 健康）状况。在小鼠模型中进行的初步研究中，我们发现了第一个蛋白质的例子， 是骨骼肌质量、质量、力量和耐力运动能力损失所必需的 衰老：转录因子ATF4。我们发现条件性基因敲除小鼠体内缺乏 ATF4 表达 骨骼肌纤维从出生起就正常发育，并在中期表现出正常的肌肉质量和功能 年龄;然而，它们能够抵抗年龄引起的肌肉质量、力量、质量和耐力的下降 锻炼能力。相反，在年轻成人骨骼肌纤维中强制表达 ATF4 就足以 诱发萎缩。此外，我们发现了两种结构不同的小分子，显着 减少与年龄相关的肌肉无力和萎缩，有趣的是，这两种小分子都会削弱 ATF4 老年骨骼肌的活动。总的来说，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，我们尚不知道 ATF4 活性的特定降低是否可以有效地应用于老年人 骨骼肌，足以治疗与年龄相关的肌肉无力和萎缩。此外，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。到 为了开始解决这些重要问题，我们提出了三个具体目标，全部使用小鼠模型。在目标 1 中，我们 将检验以下假设：老年骨骼肌纤维中 ATF4 表达急剧、有针对性地减少 小鼠将逆转与年龄相关的肌肉质量和功能的变化。在目标 2 中，我们将确定 ATF4 依赖性 与年龄相关的骨骼肌萎缩所需的 mRNA，检验 ATF4 促进的假设 通过激活某些骨骼肌基因而导致肌肉损失，这些基因的蛋白质产物是肌纤维所必需的 衰老过程中萎缩。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 至少部分负责与年龄相关的蛋白质紊乱的假设 新陈代谢是肌肉无力和萎缩的核心。通过这些研究，我们希望能够阐明 年龄相关性肌肉无力的基本分子机制和新治疗方法 萎缩症是一种致残性疾病，仅在美国就影响了数百万老年人。

项目成果

ATF4 Protects the Heart From Failure by Antagonizing Oxidative Stress.

• DOI: 10.1161/circresaha.122.321050
• 发表时间: 2022-06-24
• 期刊: CIRCULATION RESEARCH
• 影响因子: 20.1
• 作者: Wang, Xiaoding;Zhang, Guangyu;Dasgupta, Subhajit;Niewold, Erica L.;Li, Chao;Li, Qinfeng;Luo, Xiang;Tan, Lin;Ferdous, Anwarul;Lorenzi, Philip L.;Rothermel, Beverly A.;Gillette, Thomas G.;Adams, Christopher M.;Scherer, Philipp E.;Hill, Joseph A.;Wang, Zhao, V
• 通讯作者: Wang, Zhao, V

Pericyte transplantation improves skeletal muscle recovery following hindlimb immobilization.

周细胞移植可改善后肢固定后骨骼肌的恢复。

• DOI: 10.1096/fj.201802580r
• 发表时间: 2019
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Munroe,Michael;Dvoretskiy,Svyatoslav;Lopez,Amber;Leong,Jiayu;Dyle,MichaelC;Kong,Hyunjoon;Adams,ChristopherM;Boppart,MarniD
• 通讯作者: Boppart,MarniD

Loss of tRNA-modifying enzyme Elp3 activates a p53-dependent antitumor checkpoint in hematopoiesis.

• DOI: 10.1084/jem.20200662
• 发表时间: 2021-03-01
• 期刊: The Journal of experimental medicine
• 作者: Rosu A;El Hachem N;Rapino F;Rouault-Pierre K;Jorssen J;Somja J;Ramery E;Thiry M;Nguyen L;Jacquemyn M;Daelemans D;Adams CM;Bonnet D;Chariot A;Close P;Bureau F;Desmet CJ
• 通讯作者: Desmet CJ

ATF4 expression in thermogenic adipocytes is required for cold-induced thermogenesis in mice via FGF21-independent mechanisms.

• DOI: 10.1038/s41598-024-52004-8
• 发表时间: 2024-01-18
• 期刊: Scientific reports
• 影响因子: 4.6

The transcription regulator ATF4 is a mediator of skeletal muscle aging.

• DOI: 10.1007/s11357-023-00772-y
• 发表时间: 2023-08
• 期刊: GEROSCIENCE
• 影响因子: 5.6
• 作者: Miller, Matthew J.;Marcotte, George R.;Basisty, Nathan;Wehrfritz, Cameron;Ryan, Zachary C.;Strub, Matthew D.;McKeen, Andrew T.;Stern, Jennifer I.;Nath, Karl A.;Rasmussen, Blake B.;Judge, Andrew R.;Schilling, Birgit;Ebert, Scott M.;Adams, Christopher M.
• 通讯作者: Adams, Christopher M.