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

 65岁以上的人口不仅以惊人的速度增长，而且到2030年，十分之六的人将管理一种以上的慢性病，他们将占住院治疗的比例比以往任何时候都要大得多。在这一群体中，因疾病、损伤和/或手术而住院可能会损害身体活动能力，因此，老年人在住院期间及以后的身体活动能力也会受到损害。由此产生的久坐不动的生活方式可能被接受为“新常态”，最终增加骨骼肌和代谢功能障碍的风险（例如葡萄糖处置受损、胰岛素抵抗）。如果通过适当的机制干预加以预防，这些毁灭性后果既不是不可避免的，也不是必要的。一种新的机制，可能有助于物理失活诱导的胰岛素抵抗是骨骼肌内的炎症和神经酰胺的积累，启动激活的toll样受体4（TLR 4）/MyD 88信号通路。我们以前已经表明，骨骼肌TLR 4/MyD 88信号调节促炎途径和神经酰胺生物合成，而TLR 4的敲低保护肌肉免受脂质诱导的胰岛素抵抗。有趣的是，骨骼肌TLR 4、炎症和神经酰胺的增加与各种代谢紊乱如糖尿病和胰岛素抵抗有关。然而，目前尚不清楚骨骼肌TLR 4/MyD 88信号传导以及随后的炎症和神经酰胺增加是否是与老年人身体不活动引起的胰岛素抵抗相关的关键机制。Drummond博士的初步工作支持了这样一个假设，即身体不活动会增加老年人骨骼肌中的TLR 4、炎症和神经酰胺生物合成。此外，我们在小鼠实验中的初步数据表明，过度活跃的MyD 88信号转导调节由短期身体不活动引起的胰岛素抵抗。因此，Drummond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TLR 4/MyD 88信号传导是否在炎症和神经酰胺的产生中很重要，因此胰岛素抵抗由身体不活动引起。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.