Muscle Atrophy and Bone Anabolism

描述（由申请人提供）：本项目将探索一个新的假设，该假设产生于我们意想不到的观察，即在骨骼的外源性机械载荷上叠加肌肉麻痹大大增强了对载荷的成骨反应。这些数据直接挑战了该领域的核心范式，该范式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，瘫痪肌肉相对于负荷骨的位置并没有改变这种反应，证实了一种循环因子负责介导合成代谢的增强。我们随后的研究揭示了肌肉萎缩和骨合成代谢耦合的候选者，microRNA 206 （mir-206）。与通过外泌体microRNA进行细胞间信号传导的快速增长的文献以及mir-206抑制组蛋白去乙酰化酶4 （HDAC4）的能力一致，进而增强成骨细胞的分化，我们假设：肌肉麻痹会短暂上调外泌体mir-206，后者通过抑制HDAC4增强成骨细胞的分化和功能。我们将通过四个密切相关的目标来研究这篇论文

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.