Skeletal muscle secretome in Duchenne muscular dystrophy: a pivotal anti-inflammatory role of adiponectin
Skeletal muscle secretome in Duchenne muscular dystrophy: a pivotal anti-inflammatory role of adiponectin
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DOI：
10.1007/s00018-017-2465-5
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发表时间：
2017-07-01
影响因子：
8
通讯作者：
Brichard, S. M.
中科院分区：
文献类型：
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作者：
Lecompte, S.;Abou-Samra, M.;Brichard, S. M.
背景持续性炎症可加重Duchenne型肌营养不良症（DMD）的进展。在代谢综合征中降低的激素脂联素（ApN）在骨骼肌上表现出抗炎特性，并使mdx小鼠的营养不良表型恶化。在这里，我们调查是否ApN保留其抗炎作用从DMD患者获得的肌管。我们通过研究分泌组和ApN.Methods的早期事件揭开了潜在的机制，从DMD和对照患者的肌管的原代培养物进行了治疗或不通过ApN后，炎症的挑战。通过细胞因子抗体阵列和ELISA鉴定培养基中分泌的肌因子。ApN信号的早期事件进行了评估，通过废除选定的genes.Results ApN保留其抗炎特性在营养不良和控制肌管。分泌产物的分析显示，ApN下调DMD肌管中两种促炎因子（TNF α和IL 17 A）、一种可溶性受体（sTNFRII）和一种趋化因子（CCL 28）的分泌，同时上调发挥一些抗炎作用的IL-6。这些变化被解释的翻译前机制。ApN级联反应的早期事件涉及AdipoR 1（肌肉的主要受体）和AMPK-SIRT 1-PGC-1 α轴，除了肌因子谱的改变外，还导致utrophin A的上调结论ApN通过激活AdipoR 1-AMPK-SIRT 1 PGC-1 α通路，从而诱导下游肌细胞因子分泌向较少炎性分布的转变，同时上调肌营养蛋白。ApN、级联反应的早期事件和下游肌因子可能是DMD治疗的靶点。
Background Persistent inflammation exacerbates the progression of Duchenne muscular dystrophy (DMD). The hormone, adiponectin (ApN), which is decreased in the metabolic syndrome, exhibits anti-inflammatory properties on skeletal muscle and alleviates the dystrophic phenotype of mdx mice. Here, we investigate whether ApN retains its anti-inflammatory action in myotubes obtained from DMD patients. We unravel the underlying mechanisms by studying the secretome and the early events of ApN.Methods Primary cultures of myotubes from DMD and control patients were treated or not by ApN after an inflammatory challenge. Myokines secreted in medium were identified by cytokine antibody-arrays and ELISAs. The early events of ApN signaling were assessed by abrogating selected genes.Results ApN retained its anti-inflammatory properties in both dystrophic and control myotubes. Profiling of secretory products revealed that ApN downregulated the secretion of two pro-inflammatory factors (TNF alpha and IL17A), one soluble receptor (sTNFRII), and one chemokine (CCL28) in DMD myotubes, while upregulating IL-6 that exerts some anti-inflammatory effects. These changes were explained by pretranslational mechanisms. Earlier events of the ApN cascade involved AdipoR1, the main receptor for muscle, and the AMPK-SIRT1-PGC-1 alpha axis leading, besides alteration of the myokine profile, to the upregulation of utrophin A (a dystrophin analog).Conclusion ApN retains its beneficial properties in dystrophic muscles by activating the AdipoR1-AMPK-SIRT1PGC-1 alpha pathway, thereby inducing a shift in the secretion of downstream myokines toward a less inflammatory profile while upregulating utrophin. ApN, the early events of the cascade and downstream myokines may be therapeutic targets for the management of DMD.