Novel molecular mechanisms of skeletal muscle insulin resistance in physically inactive older adults

摘要 65岁以上的人口不仅以惊人的速度增长，而且因为十分之六的人将管理 到2030年，他们将占住院治疗的比例远远超过 从未有过在这一组中，因疾病、损伤和/或手术而住院可能会损害身体健康。 因此，老年人在住院期间和以后都有能力进行身体活动。 由此产生的久坐不动的生活方式可能会被接受为“新常态”，最终增加了患上糖尿病的风险。 骨骼肌和代谢功能障碍（例如葡萄糖处置受损、胰岛素抵抗）。这些 如果通过适当的基于机制的预防， 干预 一种新的机制，可能有助于身体不活动诱导的胰岛素抵抗的积累， Toll样受体4激活引发的骨骼肌内炎症和神经酰胺 （TLR4）/MyD88信号通路。我们先前已经证明，骨骼肌TLR4/MyD88信号转导 调节促炎途径和神经酰胺生物合成，而TLR4的敲低保护肌肉 对抗脂质诱导的胰岛素抵抗。有趣的是，增加的骨骼肌TLR4，炎症和 神经酰胺与各种代谢紊乱如糖尿病和胰岛素抗性有关。但 目前尚不清楚骨骼肌TLR4/MyD88信号传导和随后的炎症增加是否与 和神经酰胺是与老年人由于缺乏体力活动而引起的胰岛素抵抗相关的关键机制。 博士Drummond的初步研究支持了缺乏体力活动会增加TLR4的假设， 炎症和老年人骨骼肌中神经酰胺的生物合成。此外，我们的初步数据显示， 小鼠实验表明，过度活跃的MyD88信号调节由短- 术语身体活动不足。因此，Drummond博士和他的多学科研究团队提出， 在老年人中进行平行临床研究，并使用肌肉特异性 小鼠模型和药物干预研究，以测试骨骼肌TLR4/MyD88信号传导是否是 重要的是在生产炎症和神经酰胺，因此胰岛素抵抗引起的物理 不活动。这些发现将为开发治疗方法以预防非活动性胰岛素抵抗奠定基础。 老年人

Abstract The over-65 population is not only increasing at an alarming rate, but because six out of 10 will be managing more than one chronic condition by 2030, they will make up a much greater proportion of hospitalizations than ever before. Hospitalizations for disease, injury, and/or surgery in this group are likely to impair physical mobility and, therefore, the older adults capacity to be physically active both during hospitalization and beyond. The resulting sedentary lifestyle is likely to be accepted as the “new normal”, ultimately increasing the risk of skeletal muscle and metabolic dysfunction (e.g. impaired glucose disposal, insulin resistance). These devastating outcomes are neither inevitable nor necessary if prevented with an appropriate mechanism-based intervention. A novel mechanism that may contribute to physical inactivity-induced insulin resistance is accumulation of inflammation and ceramide within skeletal muscle initiated by activation of the toll-like receptor 4 (TLR4)/MyD88 signaling pathway. We have previously shown that skeletal muscle TLR4/MyD88 signaling regulates pro-inflammatory pathways and ceramide biosynthesis whereas knockdown of TLR4 protects muscle against lipid-induced insulin resistance. Of interest, increased skeletal muscle TLR4, inflammation and ceramide has been tied to various metabolic disturbances such as diabetes and insulin resistance. However, it is currently unknown if skeletal muscle TLR4/MyD88 signaling and the subsequent increase in inflammation and ceramide are a key mechanism associated with insulin resistance due to physical inactivity in older adults. Dr. Drummond’s preliminary work supports the hypothesis that physical inactivity increases TLR4, inflammation, and ceramide biosynthesis in skeletal muscle of older adults. Additionally, our preliminary data in mouse experiments indicate that hyperactive MyD88 signaling regulates insulin resistance caused by short- term physical inactivity. Therefore, Dr. Drummond and his multidisciplinary research team have proposed to conduct parallel clinical studies in older adults and a series of mechanistic studies using muscle-specific mouse models and drug intervention studies to test whether skeletal muscle TLR4/MyD88 signaling is important in the production of inflammation and ceramide and therefore insulin resistance caused by physical inactivity. These findings will be foundational for developing treatments to prevent insulin resistance in inactive older adults.