PDF(Pubmed)
Abstract：
Amyotrophic lateral sclerosis (ALS) is a motor neuron (MN) disease associated with progressive muscle atrophy, paralysis, and eventually death. Growing evidence demonstrates that the pathological process leading to ALS is the result of multiple altered mechanisms occurring not only in MNs but also in other cell types inside and outside the central nervous system. In this context, the involvement of skeletal muscle has been the subject of a few studies on patients and ALS animal models. In this work, by using primary myocytes derived from the ALS transgenic hSOD1(G93A) mouse model, we observed that the myogenic capability of such cells was defective compared to cells derived from control mice expressing the nonpathogenic hSOD1(WT) isoform. The correct in vitro myogenesis of hSOD1(G93A) primary skeletal muscle cells was rescued by the addition of a conditioned medium from healthy hSOD1(WT) myocytes, suggesting the existence of an in trans activity of secreted factors. To define a dataset of molecules participating in such safeguard action, we conducted comparative metabolomic profiling of a culture medium collected from hSOD1(G93A) and hSOD1(WT) primary myocytes and report here an altered secretion of amino acids and lipid-based signaling molecules. These findings support the urgency of better understanding the role of the skeletal muscle secretome in the regulation of the myogenic program and mechanisms of ALS pathogenesis and progression.
摘要：
肌萎缩侧索硬化症（ALS）是一种与进行性肌肉萎缩相关的运动神经元（MN）疾病，瘫痪最终死亡。越来越多的证据表明，导致ALS的病理过程是多种机制改变的结果，不仅发生在MNs中，而且发生在中枢神经系统内外的其他细胞类型中。在这种情况下，骨骼肌受累一直是关于患者和ALS动物模型的一些研究的主题。在这项工作中,通过使用源自ALS转基因hSOD1（G93A）小鼠模型的原代心肌细胞，我们观察到,与来自表达非致病性hSOD1(WT)同种型的对照小鼠的细胞相比,这种细胞的生肌能力是有缺陷的。通过从健康的hSOD1（WT）肌细胞中添加条件培养基，挽救了hSOD1（G93A）原代骨骼肌细胞的正确体外肌生成，表明存在分泌因子的反式活性。为了定义参与此类保障行动的分子数据集，我们对从hSOD1(G93A)和hSOD1(WT)原代心肌细胞收集的培养基进行了比较代谢组学分析,并在此报告了氨基酸和基于脂质的信号分子分泌的改变.这些发现支持了更好地了解骨骼肌分泌组在肌源性程序调节中的作用以及ALS发病机理和进展的机制的紧迫性。
