Insulin Resistance is Associated with MCP1-Mediated Macrophage Accumulation in Skeletal Muscle in Mice and Humans

Inflammation is now recognized as a major factor contributing to type 2 diabetes (T2D). However, while the mechanisms and consequences associated with white adipose tissue inflammation are well described, very little is known concerning the situation in skeletal muscle. The aim of this study was to investigate, in vitro and in vivo, how skeletal muscle inflammation develops and how in turn it modulates local and systemic insulin sensitivity in different mice models of T2D and in humans, focusing on the role of the chemokine MCP1. Here, we found that skeletal muscle inflammation and macrophage markers are increased and associated with insulin resistance in mice models and humans. In addition, we demonstrated that intra-muscular TNFα expression is exclusively restricted to the population of intramuscular leukocytes and that the chemokine MCP1 was associated with skeletal muscle inflammatory markers in these models. Furthermore, we demonstrated that exposure of C2C12 myotubes to palmitate elevated the production of the chemokine MCP1 and that the muscle-specific overexpression of MCP1 in transgenic mice induced the local recruitment of macrophages and altered local insulin sensitivity. Overall our study demonstrates that skeletal muscle inflammation is clearly increased in the context of T2D in each one of the models we investigated, which is likely consecutive to the lipotoxic environment generated by peripheral insulin resistance, further increasing MCP1 expression in muscle. Consequently, our results suggest that MCP1-mediated skeletal muscle macrophages recruitment plays a role in the etiology of T2D.

目前学界已明确，炎症是诱发2型糖尿病（type 2 diabetes, T2D）的核心危险因素。然而，尽管白色脂肪组织（white adipose tissue）炎症的相关机制与后果已被充分阐明，但针对骨骼肌（skeletal muscle）炎症的研究却相对匮乏。本研究旨在通过体外（in vitro）与体内（in vivo）实验，探究不同2型糖尿病小鼠模型及人类体内的骨骼肌炎症发生机制，以及其如何反向调控局部与全身胰岛素敏感性，并重点关注趋化因子MCP1（chemokine MCP1）的作用。
本研究发现，在小鼠模型与人类样本中，骨骼肌炎症及巨噬细胞（macrophage）标志物水平均显著升高，且与胰岛素抵抗（insulin resistance）密切相关。此外，本研究证实，肌内肿瘤坏死因子α（TNFα）的表达仅局限于肌内白细胞群体，且在上述模型中，趋化因子MCP1与骨骼肌炎症标志物显著相关。
进一步研究显示，将C2C12肌管（C2C12 myotubes）暴露于棕榈酸（palmitate）环境后，其趋化因子MCP1的分泌水平显著升高；而在转基因小鼠（transgenic mice）中实现骨骼肌特异性过表达MCP1，可诱导巨噬细胞局部招募，并改变局部胰岛素敏感性。
综上，本研究证实，在本研究所涉及的全部模型中，2型糖尿病背景下的骨骼肌炎症均显著升高，这大概率继发于外周胰岛素抵抗（peripheral insulin resistance）所诱导的脂毒性环境（lipotoxic environment），进而进一步提升肌肉内MCP1的表达水平。最终，本研究结果提示，MCP1介导的骨骼肌巨噬细胞招募在2型糖尿病的病因学（etiology）中发挥了一定作用。