Identification of a KLF5-dependent program and drug development for skeletal muscle atrophy
Identification of a KLF5-dependent program and drug development for skeletal muscle atrophy
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DOI：
10.1073/pnas.2102895118
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发表时间：
2021-08-25
影响因子：
11.1
通讯作者：
Oishi, Yumiko
中科院分区：
文献类型：
--
作者：
Liu, Lin;Koike, Hiroyuki;Oishi, Yumiko
骨骼肌萎缩是由多种疾病引起的，包括衰老、与久坐不动的生活方式和缺乏体力活动有关的废用以及恶病质。我们对肌肉萎缩的分子机制了解不足，限制了有效药物治疗和预防的目标。在这里，我们确定Kruppel样因子5（KLF 5），锌指转录因子，作为早期肌肉萎缩程序的关键介质。KLF 5在萎缩的肌管中上调，作为对地塞米松或体外模拟微重力的早期反应。骨骼肌选择性缺失Klf 5显著减弱小鼠机械去负荷诱导的肌肉萎缩。转录组和全基因组染色质可及性分析显示，KLF 5调节萎缩相关的程序，包括代谢变化和E3-泛素连接酶介导的蛋白水解，与Foxo 1协调。合成的维甲酸受体激动剂Am 80，KLF 5抑制剂，抑制地塞米松和微重力诱导的肌肉萎缩在体外和口服Am 80改善废用和地塞米松诱导的萎缩小鼠。此外，在三组独立的人类骨骼肌转录组数据中，KLF 5的表达随着年龄的增长和肌肉减少症的存在而显著增加，并与萎缩相关的泛素连接酶基因FBXO 32和TRIM 63的表达呈正相关。这些发现表明KLF 5是介导肌肉萎缩的关键转录调节因子，并且Am 80的药理学干预是一种潜在的预防性治疗。
Skeletal muscle atrophy is caused by various conditions, including aging, disuse related to a sedentary lifestyle and lack of physical activity, and cachexia. Our insufficient understanding of the molecular mechanism underlying muscle atrophy limits the targets for the development of effective pharmacologic treatments and preventions. Here, we identified Kruppel-like factor 5 (KLF5), a zinc-finger transcription factor, as a key mediator of the early muscle atrophy program. KLF5 was up-regulated in atrophying myotubes as an early response to dexamethasone or simulated microgravity in vitro. Skeletal muscle-selective deletion of Klf5 significantly attenuated muscle atrophy induced by mechanical unloading in mice. Transcriptomeand genome-wide chromatin accessibility analyses revealed that KLF5 regulates atrophy-related programs, including metabolic changes and E3-ubiquitin ligase-mediated proteolysis, in coordination with Foxo1. The synthetic retinoic acid receptor agonist Am80, a KLF5 inhibitor, suppressed both dexamethasone- and microgravityinduced muscle atrophy in vitro and oral Am80 ameliorated disuse- and dexamethasone-induced atrophy in mice. Moreover, in three independent sets of transcriptomic data from human skeletal muscle, KLF5 expression significantly increased with age and the presence of sarcopenia and correlated positively with the expression of the atrophy-related ubiquitin ligase genes FBXO32 and TRIM63. These findings demonstrate that KLF5 is a key transcriptional regulator mediating muscle atrophy and that pharmacological intervention with Am80 is a potentially preventive treatment.