Modulation of mTOR signaling as a strategy for the treatment of Pompe disease.
Modulation of mTOR signaling as a strategy for the treatment of Pompe disease.
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DOI：
10.15252/emmm.201606547
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发表时间：
2017-03
影响因子：
11.1
通讯作者：
Raben N
中科院分区：
文献类型：
--
作者：
Lim JA;Li L;Shirihai OS;Trudeau KM;Puertollano R;Raben N
雷帕霉素的机制靶点（mTOR）响应于包括生长因子和营养物在内的多种细胞外和细胞内信号而协调生物合成和分解代谢过程。这种丝氨酸/苏氨酸激酶长期以来被认为是肌肉质量的关键调节剂。最近的发现是，关于其激活/失活的决定发生在溶酶体中，这无疑将mTOR带入了溶酶体贮积病领域。在这项研究中，我们研究了mTOR通路在严重肌肉萎缩性疾病（庞贝氏症）的病理生理学中的参与，该疾病是由溶酶体糖原过度积累引起的。在这里，我们报告了患病肌肉细胞中mTOR信号转导的失调，我们专注于治疗干预的潜在位点。通过TSC敲低在庞贝氏症小鼠的整个肌肉中重新激活mTOR导致萎缩的逆转和自噬积累的显著去除。特别令人感兴趣的是，我们发现异常的mTOR信号传导可以被精氨酸逆转。这一发现可以转化为临床，并可能成为溶酶体，代谢和神经肌肉疾病的靶向治疗的范例。
Mechanistic target of rapamycin (mTOR) coordinates biosynthetic and catabolic processes in response to multiple extracellular and intracellular signals including growth factors and nutrients. This serine/threonine kinase has long been known as a critical regulator of muscle mass. The recent finding that the decision regarding its activation/inactivation takes place at the lysosome undeniably brings mTOR into the field of lysosomal storage diseases. In this study, we have examined the involvement of the mTOR pathway in the pathophysiology of a severe muscle wasting condition, Pompe disease, caused by excessive accumulation of lysosomal glycogen. Here, we report the dysregulation of mTOR signaling in the diseased muscle cells, and we focus on potential sites for therapeutic intervention. Reactivation of mTOR in the whole muscle of Pompe mice by TSC knockdown resulted in the reversal of atrophy and a striking removal of autophagic buildup. Of particular interest, we found that the aberrant mTOR signaling can be reversed by arginine. This finding can be translated into the clinic and may become a paradigm for targeted therapy in lysosomal, metabolic, and neuromuscular diseases.