RATIONALE Skeletal muscle wasting with accompanying cachexia is a life threatening complication in congestive heart failure. The molecular mechanisms are imperfectly understood, although an activated renin-angiotensin aldosterone system 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 D1 (PKD1). OBJECTIVE To elucidate the molecular mechanism of Ang II-induced skeletal muscle wasting. METHODS AND RESULTS 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 small interfering RNA prevented Ang II-induced MuRF1 expression and atrophy. The histone deacetylase-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. CONCLUSION We propose that elevated Ang II serum concentrations, as occur in patients with congestive heart failure, could activate the PKD1/HDAC5/TFEB/MuRF1 pathway to induce skeletal muscle wasting.

中文翻译：

---

血管紧张素II通过激活TFEB介导的MuRF1表达诱导骨骼肌萎缩。

理性的骨骼肌消瘦伴有恶病质是充血性心力衰竭的危及生命的并发症。尽管涉及活化的肾素-血管紧张素醛固酮系统，但分子机制尚不完全清楚。血管紧张素（Ang）II部分地通过增加富含肌肉的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D1（PKD1）。目的阐明血管紧张素Ⅱ引起的骨骼肌消瘦的分子机制。方法和结果cDNA表达筛选确定了溶酶体水解酶配体转录因子EB（TFEB）是人类MuRF1启动子的新型调节子。TFEB通过保守的E-box元件通过转录控制MuRF1在调节Ang II诱导的骨骼肌萎缩中起关键作用。用小的干扰RNA抑制TFEB可以防止Ang II诱导的MuRF1表达和萎缩。直接与TFEB结合并共定位的组蛋白脱乙酰基酶5（HDAC5）抑制TFEB诱导的MuRF1表达。HDAC5对TFEB的抑制作用被PKD1逆转，后者与HDAC5相关并介导其核输出。骨骼肌细胞中缺乏PKD1的小鼠对Ang II诱导的肌肉消瘦具有抵抗力。结论我们认为，充血性心力衰竭患者发生的Ang II血清浓度升高可以激活PKD1 / HDAC5 / TFEB / MuRF1途径，从而引起骨骼肌消耗。抑制TFEB诱导的MuRF1表达。HDAC5对TFEB的抑制作用被PKD1逆转，后者与HDAC5相关并介导其核输出。骨骼肌细胞中缺乏PKD1的小鼠对Ang II诱导的肌肉消瘦具有抵抗力。结论我们认为充血性心力衰竭患者发生的Ang II血药浓度升高可能会激活PKD1 / HDAC5 / TFEB / MuRF1途径引起骨骼肌消耗。抑制TFEB诱导的MuRF1表达。HDAC5对TFEB的抑制作用被PKD1逆转，后者与HDAC5相关并介导其核输出。骨骼肌细胞中缺乏PKD1的小鼠对Ang II诱导的肌肉消瘦具有抵抗力。结论我们认为充血性心力衰竭患者发生的Ang II血药浓度升高可能会激活PKD1 / HDAC5 / TFEB / MuRF1途径引起骨骼肌消耗。