A Small-Molecule Approach to Restore a Slow-Oxidative Phenotype and Defective CaMKIIβ Signaling in Limb Girdle Muscular Dystrophy.
A Small-Molecule Approach to Restore a Slow-Oxidative Phenotype and Defective CaMKIIβ Signaling in Limb Girdle Muscular Dystrophy.
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DOI：
10.1016/j.xcrm.2020.100122
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发表时间：
2020-10-20
期刊：
影响因子：
--
通讯作者：
Spencer MJ
中科院分区：
文献类型：
--
作者：
Liu J;Campagna J;John V;Damoiseaux R;Mokhonova E;Becerra D;Meng H;McNally EM;Pyle AD;Kramerova I;Spencer MJ
CAPN 3的突变导致肢带型肌营养不良症R1（LGMDR 1，以前称为LGMD 2A），并导致进行性和衰弱性肌肉萎缩。钙蛋白酶3缺乏与CaMKIIβ信号传导受损和编码慢氧化肌肉表型的转录程序钝化有关。我们对CaMKII（Myl 2）的靶标进行了高通量筛选，以鉴定克服这种信号传导缺陷的化合物;在LGMDR 1的Capn 3敲除（C3 KO）模型中对4种化合物进行了体内测试。领先的化合物AMBMP表现出良好的暴露性，并能够在体内逆转LGMDR 1表型，包括改善氧化性能，增加慢纤维尺寸和增强运动性能。AMBMP还激活了CaMKIIβ信号，但它没有改变已知与肌肉生长相关的其他途径。因此，AMBMP处理激活CaMKII并代谢性地将骨骼肌重编程为慢肌表型。这些概念验证研究为开发LGMDR 1治疗方法提供了支持。运动诱导钙钙调蛋白激酶激活和适应性基因表达这种信号传导在Capn 3缺乏中被钝化，导致肢带型肌营养不良症一种小分子，AMBMP，是一种运动模拟物，诱导这些途径AMBMP使Capn 3 −/−表型正常化未能正确诱导运动激活的信号传导途径，并促进慢-肌肉中的氧化基因表达程序导致肢带型肌营养不良症。Liu等人报告说，一个小分子可以激活这些途径，并恢复有缺陷的信号和转录模式，需要扭转肌肉表型。
Mutations in CAPN3 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 (Myl2) to identify compounds to override this signaling defect; 4 were tested in vivo in the Capn3 knockout (C3KO) model of LGMDR1. The leading compound, AMBMP, showed good exposure and was able to reverse the LGMDR1 phenotype in vivo, 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. Exercise induces calcium calmodulin kinase activation and adaptive gene expression This signaling is blunted in Capn3 deficiency, causing limb girdle muscular dystrophy A small molecule, AMBMP, is an exercise mimetic that induces these pathways AMBMP normalizes the Capn3−/− phenotype Failure to properly induce the signaling pathways that are activated by exercise and which promote the slow-oxidative gene expression program in muscle leads to limb girdle muscular dystrophy. Liu et al. report that a small molecule could activate these pathways and restore both the defective signaling and transcriptional patterns needed to reverse the muscle phenotype.
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