Muscle Atrophy and Bone Anabolism

描述（由申请人提供）：本项目将探索一种新的假设，该假设源于我们的意外观察，即在骨的外源性机械负荷上叠加肌肉麻痹，极大地增强了对负荷的成骨反应。这些数据直接挑战了该领域的中心范式，这反映了从组织到分子水平，肌肉和骨骼萎缩和肥大并行的共识。我们的初步研究进一步表明，相对于负载骨的麻痹肌肉的位置并没有改变这种反应，证实了循环因子负责介导增强的抗张力。我们随后的研究揭示了一种偶联肌肉萎缩和骨愈合的候选者，microRNA 206（mir-206）。与关于经由外泌体microRNA的细胞间信号传导的快速扩展的文献以及mir-206抑制组蛋白脱乙酰酶4（HDAC 4）（其进而增强成骨细胞分化）的已证实能力一致，我们假设：肌肉麻痹瞬时上调外泌体mir-206，其经由HDAC 4的抑制增强成骨细胞分化和功能。我们将通过四个密切相关的S来探讨这篇论文。目标，每个 并有相应的子假设。体内实验结果表明，S.目的#1和#2旨在证明肌肉麻痹诱导的细胞信号传导通过血清内的外来体瞬时增强正在进行的成骨细胞分化和功能，观察到的合成代谢增强可以独立于负荷诱导的成骨细胞活化而实现，并且可以在小梁和皮质骨中诱导反应。我们将使用体外方法来证实外泌体mir-206通过抑制HDAC 4的翻译来增强成骨细胞的分化和功能。目的#3），我们将证明该途径的下游体内靶向（通过HDAC 4抑制）能够复制增强的骨粘附，而不需要诱导肌肉麻痹（S。目标4）。如果该项目成功，我们相信这些数据将从根本上改变我们对肌肉和骨骼如何在分子、细胞和组织水平上相互作用的概念，并将使这一途径成为能够增强骨形态的最终临床干预措施。

DESCRIPTION (provided by applicant): This project will explore a novel hypothesis that arose from our unexpected observation that superimposing muscle paralysis upon exogenous mechanical loading of bone greatly augments the osteogenic response to loading. These data directly challenge a central paradigm in the field, which reflects the consensus that, from the tissue to molecular levels, muscle and bone atrophy and hypertrophy in parallel. Our preliminary studies further demonstrated that the location of the paralyzed muscle relative to the loaded bone did not alter this response, confirming that a circulating factor was responsible for mediating the enhanced anabolism. Our subsequent studies have revealed a candidate for coupling muscle atrophy and bone anabolism, microRNA 206 (mir-206). Consistent with the rapidly expanding literature regarding cell-to-cell signaling via exosomal microRNA and the demonstrated ability of mir-206 to suppress histone deacetylase 4 (HDAC4) which, in turn, enhances osteoblast differentiation, we hypothesize that: muscle paralysis transiently upregulates exosomal mir-206 which, via suppression of HDAC4, enhances osteoblast differentiation and function. We will pursue this thesis through four closely related S. Aims, each with a corresponding sub- hypothesis. The in vivo experiments of S. Aims #1 and #2 are designed to demonstrate that cellular signaling induced by muscle paralysis transiently enhances ongoing osteoblast differentiation and function via exosomes within the serum, that the observed anabolic augmentation can be achieved independently of loading induced osteoblast activation, and that the response can be induced in both trabecular and cortical bone. We will use in vitro approaches to confirm that exosomal mir-206 serves to enhance osteoblast differentiation and function by suppressing translation of HDAC4 (S. Aim #3) and we will demonstrate that downstream in vivo targeting of this pathway (via HDAC4 inhibition) is able to replicate enhanced bone anabolism without the necessity of inducing muscle paralysis (S. Aim #4). If the project is successful, we believe these data would fundamentally alter our conceptualization of how muscle and bone interact at the molecular, cellular, and tissue levels and would enable novel targeting of this pathway as an eventual clinical intervention capable of enhancing bone morphology.