Absence of MyD88 from Skeletal Muscle Protects Female Mice from Inactivity-Induced Adiposity and Insulin Resistance
Absence of MyD88 from Skeletal Muscle Protects Female Mice from Inactivity-Induced Adiposity and Insulin Resistance
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DOI：
10.1002/oby.22759
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发表时间：
2020-02-28
期刊：
影响因子：
6.9
通讯作者：
Drummond, Micah J.
中科院分区：
文献类型：
--
作者：
Mahmassani, Ziad S.;Reidy, Paul T.;Drummond, Micah J.
目的不活动和炎症与肥胖和胰岛素抵抗有关。假设MyD 88（介导炎症）从肌肉中敲除（MusMyD 88（-/-））将防止，而miR 146 a（-/-）（MyD 88抑制剂）将加剧，不活动诱导的代谢disorders.Methods Cre对照，MusMyD 88（-/-）和miR 146 a（-/-）小鼠给予跑轮5周以模拟活动表型。然后，将一半放入小小鼠笼（SMC）中限制运动8天。评估身体组成、肌肉（H-3）2-脱氧葡萄糖摄取、内脏脂肪组织学和组织重量（后肢肌肉、内脏脂肪和肝脏）。在骨骼肌和内脏脂肪中，对雌性MusMyD 88（-/-）和Cre对照SMC小鼠进行RNA测序和线粒体功能。结果SMC诱导肥胖、高胰岛素血症和肌肉胰岛素刺激的葡萄糖摄取，miR 146 a（-/-）小鼠的情况恶化。在雌性中，MusMyD 88（-/-）小鼠受到保护。雌性MusMyD 88（-/-）小鼠在SMC期间（与Cre-control相比）表现出较高的Igf 1和降低的Ip 6 k3和Trim 63肌肉表达。内脏脂肪转录物变化对应于脂质代谢改善、脂肪膨胀减少（Gulp 1向上箭头、Anxa 2向下箭头、Ehd 1向下箭头）和继发性炎症（Hmox 1向下箭头）以及beiging增加（Fgf 10向上箭头）。结论整体miR 146 a（-/-）加重了雌性小鼠的失活诱导的脂肪增加和肌肉胰岛素抵抗，而MusMyD 88（-/-）可预防雌性小鼠的胰岛素抵抗。
Objective Inactivity and inflammation are linked to obesity and insulin resistance. It was hypothesized that MyD88 (mediates inflammation) knockout from muscle (MusMyD88(-/-)) would prevent, whereas miR146a(-/-) (MyD88 inhibitor) would exacerbate, inactivity-induced metabolic disturbances.Methods Cre-control, MusMyD88(-/-), and miR146a(-/-) mice were given running wheels for 5 weeks to model an active phenotype. Afterward, half were placed into a small mouse cage (SMC) to restrict movement for 8 days. Body composition, muscle (H-3)2-deoxyglucose uptake, visceral fat histology, and tissue weight (hind limb muscles, visceral fat, and liver) were assessed. In skeletal muscle and visceral fat, RNA sequencing and mitochondrial function were performed on female MusMyD88(-/-) and Cre-control SMC mice.Results The SMC induced adiposity, hyperinsulinemia, and muscle insulin-stimulated glucose uptake, which was worsened in miR146a(-/-) mice. In females, MusMyD88(-/-) mice were protected. Female MusMyD88(-/-) mice during the SMC period (vs. Cre-control) exhibited higher Igf1 and decreased Ip6k3 and Trim63 muscle expression. Visceral fat transcript changes corresponded to improved lipid metabolism, decreased adipose expansion (Gulp1 up arrow, Anxa2 down arrow, Ehd1 down arrow) and meta-inflammation (Hmox1 down arrow), and increased beiging (Fgf10 up arrow). Ralgapa2, negative regulator of GLUT4 translocation, and inflammation-related gene 993011J21Rik2 were decreased in both muscle and fat.Conclusions Whole-body miR146a(-/-) exacerbated inactivity-induced fat gain and muscle insulin resistance, whereas MusMyD88(-/-) prevented insulin resistance in female mice.