Angiotensin II Induces Skeletal Muscle Atrophy by Activating TFEB-Mediated MuRF1 Expression.
Angiotensin II Induces Skeletal Muscle Atrophy by Activating TFEB-Mediated MuRF1 Expression.
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DOI：
10.1161/circresaha.114.305393
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发表时间：
2015-08-14
影响因子：
20.1
通讯作者：
Fielitz J
中科院分区：
文献类型：
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作者：
Du Bois P;Pablo Tortola C;Lodka D;Kny M;Schmidt F;Song K;Schmidt S;Bassel-Duby R;Olson EN;Fielitz J
骨骼肌萎缩伴有恶病质是充血性心力衰竭（CHF）的一种危及生命的并发症。尽管涉及激活的肾素-血管紧张素醛固酮系统（RAAS），但其分子机制尚不完全清楚。血管紧张素 (Ang) II 部分通过增加肌肉富集的 E3 泛素连接酶肌肉 RING-finger-1 (MuRF1) 表达来诱导骨骼肌萎缩，这可能涉及蛋白激酶 -D 1 (PKD1)。阐明血管紧张素II诱导骨骼肌萎缩的分子机制。 cDNA 表达筛选鉴定出溶酶体水解酶协调转录因子 EB (TFEB) 是人类 MuRF1 启动子的新型调节因子。 TFEB 通过保守的 E-box 元件对 MuRF1 进行转录控制，在调节 Ang II 诱导的骨骼肌萎缩中发挥关键作用。用 siRNA 抑制 TFEB 可阻止 Ang II 诱导的 MuRF1 表达和萎缩。组蛋白脱乙酰酶 5 (HDAC5) 直接与 TFEB 结合并共定位，抑制 TFEB 诱导的 MuRF1 表达。 HDAC5 对 TFEB 的抑制可被 PKD1 逆转，PKD1 与 HDAC5 相关并介导其核输出。骨骼肌细胞中缺乏 PKD1 的小鼠能够抵抗 Ang II 诱导的肌肉萎缩。我们认为，CHF 患者中 Ang II 血清浓度升高可能会激活 PKD1/HDAC5/TFEB/MuRF1 通路，从而诱导骨骼肌萎缩。
Skeletal-muscle wasting with accompanying cachexia is a life threatening complication in congestive heart failure (CHF). The molecular mechanisms are imperfectly understood, although an activated renin-angiotensin aldosterone system (RAAS) has been implicated. Angiotensin (Ang) II induces skeletal muscle atrophy in part by increased muscle-enriched E3 ubiquitin ligase muscle RING-finger-1 (MuRF1) expression, which may involve protein kinase-D 1 (PKD1). To elucidate the molecular mechanism of Ang II-induced skeletal muscle wasting. A cDNA expression screen identified the lysosomal hydrolase-coordinating transcription factor EB (TFEB) as novel regulator of the human MuRF1-promoter. TFEB played a key role in regulating Ang II-induced skeletal muscle atrophy by transcriptional control of MuRF1 via conserved E-box elements. Inhibiting TFEB with siRNA prevented Ang II-induced MuRF1 expression and atrophy. The histone deactylase-5 (HDAC5), which was directly bound to and colocalized with TFEB, inhibited TFEB-induced MuRF1 expression. The inhibition of TFEB by HDAC5 was reversed by PKD1, which was associated with HDAC5 and mediated its nuclear export. Mice lacking PKD1 in skeletal myocytes were resistant to Ang II-induced muscle wasting. We propose that elevated Ang II serum concentrations, as occur in CHF patients, could activate the PKD1/HDAC5/TFEB/MuRF1 pathway to induce skeletal muscle wasting.