The role of the gut microbiota in sarcopenia

摘要 老年人虚弱的一个关键决定因素是骨骼肌减少，即与年龄相关的骨骼肌质量下降和 功能。最近的估计表明，多达三分之一的老年人口可能患有虚弱。脆弱 经常导致功能独立性的丧失，是老年人跌倒的主要危险因素之一。在……里面 事实上，随着预期寿命的不断增加，保持肌肉力量是一个重要因素 有助于提高生活质量。虽然石棺减少的病因仍有待确定，但建议 致病因素包括失去神经和运动单位衰退、氧化应激、异常自噬。 和炎症。有新的证据表明肠道-骨骼肌轴的存在。在…的基础上 在这种联系中，有很多人猜测肠道微生物区系的失调可能在 骨质疏松症的发展。虽然已经提出了一些看似合理的机制，通过这些机制，生态失调可能 与骨质疏松症的发展有关，但支持这一点的直接证据仍然很少 机械装置。这项探索性拨款的目的是检验肠道微生物区系失调的假设 通过TLR4诱导骨骼肌合成代谢抵抗状态促进骨质疏松症 MTORC1信号的过度激活。为了验证这一假设，将追求以下目标：目标1： 确定老年小鼠的肠道微生物区系是否可以诱导成年小鼠的骨骼减少；目标2：确定 成年小鼠的肠道微生物群可以挽救老年小鼠的石棺减少症。如果拟议的实验结果 提供证据支持这一假设，未来的R01应用程序将寻求严格测试所提出的 通过确定骨骼肌特异性TLR4基因敲除是否可以预防骨质疏松症的机制 肠道微生物区系失调引起的全身炎症。

Summary A key determinant of geriatric frailty is sarcopenia, the age-associated loss of skeletal muscle mass and function. Recent estimates indicate that up to one-third of the elderly population may suffer from frailty. Frailty often leads to loss of functional independence and is among the leading risk factors for falls in the elderly. In fact, as life expectancy continues to increase, the maintenance of muscle strength is an important factor that contributes to a higher quality of life. Although the etiology of sarcopenia remains to be determined, proposed contributing factors include the loss of innervation and motor unit decline, oxidative stress, aberrant autophagy and inflammation. There is emerging evidence for the existence of a gut-skeletal muscle axis. On the basis of this connection, there has been much speculation that dysbiosis of the gut microbiota might have a role in the development of sarcopenia. While plausible mechanisms have been proposed through which dysbiosis might contribute to the development of sarcopenia, there remains a paucity of direct evidence to support such mechanisms. The purpose of this exploratory grant is to test the hypothesis that dysbiosis of the gut microbiota promotes sarcopenia by inducing a state of anabolic resistance in skeletal muscle through TLR4 hyperactivation of mTORC1 signaling. To test this hypothesis, the following aims will be pursued: Aim 1: Determine if the gut microbiota from aged mice can induce sarcopenia in adult mice; Aim 2: Determine if the gut microbiota from adult mice can rescue sarcopenia in old mice. If the results of the proposed experiments provide evidence to support the hypothesis, a future R01 application will seek to rigorously test the proposed mechanism by determining if a skeletal muscle-specific TLR4 knockout prevents sarcopenia despite low-grade systemic inflammation induced by gut microbiota dysbiosis.