Proinflammatory macrophages impair skeletal muscle differentiation in obesity through secretion of tumor necrosis factor-alpha via sustained activation of p38 mitogen-activated protein kinase
Proinflammatory macrophages impair skeletal muscle differentiation in obesity through secretion of tumor necrosis factor-alpha via sustained activation of p38 mitogen-activated protein kinase
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促炎性巨噬细胞通过持续激活 p38 丝裂原激活蛋白激酶分泌肿瘤坏死因子-α，从而损害肥胖患者的骨骼肌分化
DOI：
10.1002/jcp.27012
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发表时间：
2019
影响因子：
5.6
通讯作者：
Liu Jiankang
中科院分区：
文献类型：
--
作者：
Wang Xueqiang;Zhao Daina;Cui Yajuan;Lu Shemin;Gao Dan;Liu Jiankang
肥胖与骨骼肌损失和肌肉生成受损有关。肥胖引起骨骼肌中促炎巨噬细胞浸润增加，并与肌肉胰岛素抵抗有关。然而，浸润的巨噬细胞是否有助于肥胖诱导的肌肉损失尚不清楚。在这项研究中，我们研究了喂食高脂肪饮食16周的肥胖小鼠的股四头肌（QC）、腓肠肌、胫骨前肌和比目鱼肌中的巨噬细胞和肌肉分化标志物。然后，我们在体外研究了巨噬细胞分泌因子对成肌细胞分化的影响和中介作用。我们发现，与其他三个肌肉组相比，QC肌肉中的促炎巨噬细胞标志物（F4/80和CD11c）水平显著升高。与促炎巨噬细胞浸润水平升高相一致，QC肌中肌肉分化因子MYOD1和肌球蛋白重链的表达也显著降低。在体外研究中，用Raw 264.7巨噬细胞条件培养基（CM）处理C2C12成肌细胞可显著促进细胞增殖并抑制成肌细胞分化。在Raw 264.7巨噬细胞CM中，肿瘤坏死因子α （TNF‐α）的中和逆转了成肌细胞分化的减少。最后，我们发现巨噬细胞CM和TNF‐α均诱导C2C12成肌细胞中p38丝裂原活化蛋白激酶（MAPK）的持续激活。总之，我们的研究结果表明，促炎巨噬细胞的浸润增加可能通过p38 MAPK信号通路分泌炎症细胞因子TNF - α，从而导致肥胖诱导的肌肉损失。
Obesity is associated with skeletal muscle loss and impaired myogenesis. Increased infiltration of proinflammatory macrophages in skeletal muscle is noted in obesity and is associated with muscle insulin resistance. However, whether the infiltrated macrophages can contribute to obesity‐induced muscle loss is unclear. In this study, we investigate macrophage and muscle differentiation markers in the quadriceps (QC), gastrocnemius, tibia anterior, and soleus muscles from obese mice that were fed a high‐fat diet for 16 weeks. Then, we examined the effect and mediator of macrophage‐secreted factors on myoblast differentiation in vitro. We found markedly increased levels of proinflammatory macrophage markers (F4/80 and CD11c) in the QC muscle compared with the other three muscle groups. Consistent with the increased levels of proinflammatory macrophage infiltration, the QC muscle also showed a significant reduction in the expression of muscle differentiation makers MYOD1 and myosin heavy chain. In in vitro studies, treatment of C2C12 myoblasts with Raw 264.7 macrophage‐conditioned medium (CM) significantly promoted cell proliferation and inhibited myoblast differentiation. Neutralization of tumor necrosis factor α (TNF‐α) in Raw 264.7 macrophage CM reversed the reduction of myoblast differentiation. Finally, we found that both macrophage CM and TNF‐α induced sustained activation of p38 mitogen‐activated protein kinase (MAPK) in C2C12 myoblasts. Together, our findings suggest that the increased infiltration of proinflammatory macrophages could contribute toward obesity‐induced muscle loss by secreting inflammatory cytokine TNF‐α via the p38 MAPK signaling pathway.