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

 描述(申请人提供)：65岁以上的人口不仅在以惊人的速度增长，而且由于到2030年，十分之六的人将患有一种以上的慢性病，他们在住院治疗中所占的比例将比以往任何时候都大得多。在这一群体中，因疾病、受伤和/或手术而住院可能会损害身体活动能力，因此，老年人在住院期间和住院后的身体活动能力都会受到影响。由此产生的久坐不动的生活方式很可能被接受为“新常态”，最终增加骨骼肌和代谢功能障碍(如葡萄糖代谢受损、胰岛素抵抗)的风险。如果通过适当的基于机制的干预来防止这些破坏性结果，这些结果既不是不可避免的，也不是必要的。Toll样受体4(Toll-like Receptor 4，TLR4)/MyD88信号通路的激活导致炎症和神经酰胺在骨骼肌内积聚，这可能是导致运动缺乏诱导胰岛素抵抗的一种新机制。我们之前已经证明，骨骼肌TLR4/MyD88信号调节促炎通路和神经酰胺的生物合成，而TLR4的敲除可以保护肌肉免受脂质诱导的胰岛素抵抗。有趣的是，骨骼肌TLR4、炎症和神经酰胺的增加与各种代谢紊乱有关，如糖尿病和胰岛素抵抗。然而，目前尚不清楚骨骼肌TLR4/MyD88信号以及随后炎症和神经酰胺的增加是否是老年人由于缺乏运动而导致的胰岛素抵抗的关键机制。德拉蒙德博士的初步工作支持这样一种假设，即缺乏运动会增加老年人骨骼肌中TLR4、炎症和神经酰胺的生物合成。此外，我们在小鼠实验中的初步数据表明，过度活跃的MyD88信号调节短期不活动引起的胰岛素抵抗。因此，德拉蒙德博士和他的多学科研究团队提议在老年人中进行平行的临床研究，并使用肌肉特异性小鼠模型和药物干预研究进行一系列机制研究，以测试骨骼肌TLR4/MyD88信号是否在炎症和神经酰胺的产生中起重要作用，从而导致身体不活动导致胰岛素抵抗。这些发现将为开发预防不活跃老年人胰岛素抵抗的治疗方法奠定基础。

 DESCRIPTION (provided by applicant): 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 adult's 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.