Muscle Atrophy and Bone Anabolism

肌肉萎缩和骨合成代谢

• 批准号: 9243976
• 负责人: TED S. GROSS
• 金额: $ 33.99万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9243976
• 关键词: Adverse effects; Anabolism; Atrophic; Botulinum Toxins; Cells; Clinical; Consensus; Coupling; Data; Dependency; Exercise; Failure; Gene Targeting; Goals; HDAC4 gene; Hypertrophy; In Vitro; Injection of therapeutic agent; Intervention; Intramuscular; Literature; Location; Mechanics; Mediating; MicroRNAs; Molecular; Morphology; Muscle; Muscular Atrophy; Osteoblasts; Osteogenesis; Outcome; Paralysed; Pathway interactions; Pharmacology; Physiology; Regimen; Risk; Series; Serum; Signal Pathway; Signal Transduction; Site; Time; Tissues; Translations; Up-Regulation; alpha Toxin; bone; bone loss; cortical bone; data modeling; design; exosome; experimental study; in vivo; mechanical load; mouse model; novel; osteoblast differentiation; osteogenic; public health relevance; response; skeletal; substantia spongiosa; therapeutic development; tibia

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.

描述（由申请人提供）：该项目将探索一个新的假设，该假设源自我们意想不到的观察，即在骨骼的外源机械负荷上叠加肌肉麻痹会大大增强对负荷的成骨反应。这些数据直接挑战了该领域的一个中心范式，它反映了这样的共识：从组织到分子水平，肌肉和骨骼萎缩和肥大是并行的。我们的初步研究进一步表明，瘫痪肌肉相对于负载骨骼的位置不会改变这种反应，证实循环因子负责介导增强的合成代谢。我们随后的研究揭示了一种耦合肌肉萎缩和骨合成代谢的候选分子，microRNA 206 (mir-206)。与有关通过外泌体 microRNA 进行细胞间信号传导的快速增加的文献一致，以及 mir-206 抑制组蛋白脱乙酰酶 4 (HDAC4) 进而增强成骨细胞分化的能力，我们假设：肌肉麻痹短暂上调外泌体 mir-206，而 mir-206 通过抑制 HDAC4，增强成骨细胞分化， 功能。我们将通过四个密切相关的 S. 目标来研究本论文，每个目标 以及相应的子假设。 S.Aims #1 和 #2 的体内实验旨在证明，肌肉麻痹诱导的细胞信号传导可通过血清内的外泌体暂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载诱导的成骨细胞激活而实现，并且可以在小梁骨和皮质骨中诱导反应。我们将使用体外方法来确认外泌体 mir-206 通过抑制 HDAC4 的翻译来增强成骨细胞分化和功能 (S. Aim #3)，并且我们将证明该通路的下游体内靶向（通过 HDAC4 抑制）能够复制增强的骨合成代谢，而无需诱导肌肉麻痹 (S. Aim #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，并将使该途径成为能够增强骨形态的最终临床干预的新目标。