Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China.
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.
J Cell Physiol. 2019 Mar;234(3):2566-2580. doi: 10.1002/jcp.27012. Epub 2018 Sep 27.
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.
肥胖与骨骼肌丢失和肌生成受损有关。在肥胖中，骨骼肌中促炎巨噬细胞的浸润增加，并与肌肉胰岛素抵抗有关。然而，浸润的巨噬细胞是否能导致肥胖引起的肌肉丢失尚不清楚。在这项研究中，我们研究了肥胖小鼠（喂食高脂肪饮食 16 周）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，我们研究了巨噬细胞分泌因子对体外成肌细胞分化的影响及其介质。我们发现，与其他三组肌肉相比，QC 肌肉中促炎巨噬细胞标志物（F4/80 和 CD11c）的水平显著升高。与促炎巨噬细胞浸润水平增加一致，QC 肌肉中肌肉分化标志物 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 中中和肿瘤坏死因子-α（TNF-α）可逆转成肌细胞分化的减少。最后，我们发现巨噬细胞 CM 和 TNF-α均可诱导 C2C12 成肌细胞中 p38 丝裂原活化蛋白激酶（MAPK）的持续激活。综上所述，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 信号通路分泌炎性细胞因子 TNF-α导致肥胖引起的肌肉丢失。
