小分子方法恢复肢带型肌肉营养不良中的缓慢氧化表型和缺陷的 CaMKIIβ 信号。
A Small-Molecule Approach to Restore a Slow-Oxidative Phenotype and Defective CaMKIIβ Signaling in Limb Girdle Muscular Dystrophy.
机构信息
Department of Neurology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, USA.
Department of Pharmacology, David Geffen School of Medicine and Molecular Screening Shared Resource, Crump Imaging Institute, University of California, Los Angeles, Los Angeles, CA, USA.
出版信息
Cell Rep Med. 2020 Oct 20;1(7):100122. doi: 10.1016/j.xcrm.2020.100122.
Mutations in cause limb girdle muscular dystrophy R1 (LGMDR1, formerly LGMD2A) and lead to progressive and debilitating muscle wasting. Calpain 3 deficiency is associated with impaired CaMKIIβ signaling and blunted transcriptional programs that encode the slow-oxidative muscle phenotype. We conducted a high-throughput screen on a target of CaMKII () to identify compounds to override this signaling defect; 4 were tested in the knockout (C3KO) model of LGMDR1. The leading compound, AMBMP, showed good exposure and was able to reverse the LGMDR1 phenotype , including improved oxidative properties, increased slow fiber size, and enhanced exercise performance. AMBMP also activated CaMKIIβ signaling, but it did not alter other pathways known to be associated with muscle growth. Thus, AMBMP treatment activates CaMKII and metabolically reprograms skeletal muscle toward a slow muscle phenotype. These proof-of-concept studies lend support for an approach to the development of therapeutics for LGMDR1.
导致肢带型肌肉营养不良症 R1（LGMDR1，以前称为 LGMD2A）的突变，并导致进行性和衰弱性肌肉消耗。钙蛋白酶 3 缺乏与 CaMKIIβ 信号受损以及编码慢氧化肌表型的转录程序减弱有关。我们对 CaMKII 的一个靶标进行了高通量筛选，以鉴定能够克服这种信号缺陷的化合物；其中 4 种化合物在 LGMDR1 的 敲除（C3KO）模型中进行了测试。领先的化合物 AMBMP 表现出良好的暴露度，并且能够逆转 LGMDR1 表型，包括改善氧化特性、增加慢肌纤维大小和增强运动表现。AMBMP 还激活了 CaMKIIβ 信号，但它没有改变与肌肉生长有关的其他已知途径。因此，AMBMP 治疗激活了 CaMKII，并使骨骼肌肉向慢肌表型进行代谢重编程。这些概念验证研究为开发 LGMDR1 治疗方法提供了支持。
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