Muscle-Bone Endocrine Axis

描述（由申请人提供）： 传统上，肌肉-骨骼关系被认为主要由机械因素驱动。然而，基于骨骼可以作为内分泌器官的观察，肌肉可以产生调节性“肌因子”，以及我们新的初步数据，我们在本申请中提出骨骼和肌肉作为内分泌器官，在健康和疾病中相互影响。我们发现，与对照小鼠相比，Lrp 5突变导致高骨量表型的小鼠显示出增强的心血管收缩功能，但意外地损害了骨骼肌收缩力。这导致了范式转换假说，即骨可以作为内分泌器官，向肌肉（无论是骨骼肌、平滑肌还是心肌）发送调节信号，并且还存在一种相互关系，肌肉可以独立于机械负荷调节骨量和强度。将使用整个生物体和体外方法对骨骼-肌肉内分泌轴的这一假设进行检验，如两个具体目标所述： 具体目标1。确定骨骼是否可以调节肌肉质量、力量和收缩功能，具体目标2。确定肌肉是否可以独立于机械负荷调节骨量和功能。两个研究团队，一个在骨生物学领域，一个在肌肉生物学领域，将利用工具，方法和综合专业知识，共同努力实现这些目标。这个新提出的肌肉骨骼内分泌研究小组将得到我们各部门现有基础设施和UMKC矿化组织研究中心的支持。我们的工作是创新和突破性的，可以随时部署，以加快在这一领域的研究。我们研究团队的建立和这些目标的实现将对肌肉骨骼疾病产生重大影响。例如，肌肉减少症和骨质疏松症是老年人中的严重健康威胁，并且是使人衰弱的损伤、丧失独立性和生活质量降低的主要原因。肌肉和骨骼疾病的潜在相互后果以及它们如何影响衰老期间的整体健康和疾病尚不清楚。因此，这项新的研究应该具有很高的影响力，并可能导致发现新的因素，这些因素可能是预防骨骼和肌肉疾病的治疗干预的目标。

DESCRIPTION (provided by applicant): Traditionally, the muscle-bone relationship has been assumed to be driven mainly by mechanical factors. Nevertheless, based on observations that bone can act as an endocrine organ, that muscle can produce regulatory 'myokines', and our new preliminary data, we propose in this application that bone and muscle act as endocrine organs that influence each other in health and disease. We found that mice with the Lrp5 mutation leading to a high bone mass phenotype, showed enhanced cardiovascular contractile function compared to control mice, but unexpectedly impaired skeletal muscle contractile force. This led to the paradigm-shifting hypothesis that bone can act as an endocrine organ, sending regulatory signals to muscles, whether skeletal, smooth, or cardiac, and that a reciprocal relationship also exists by which muscle can regulate bone mass and strength independent of mechanical loading. This hypothesis of a bone-muscle endocrine axis will be tested using both whole organism and in vitro approaches as outlined in two specific aims: Specific Aim 1. To determine if bone can regulate muscle mass, strength, and contractile function and Specific Aim 2. To determine if muscle can regulate bone mass and function independent of mechanical loading. Two teams of investigators, one in the field of bone biology and one in the field of muscle biology, will utilize the tools, approaches, and combined expertise to work collaboratively towards accomplishing these aims. This newly proposed Muscle-Bone Endocrine Research Group will be supported by the existing infrastructure of our various departments and by the UMKC Center for the Study of Mineralized Tissue. Our work is innovative and ground-breaking and can be readily deployed to accelerate research in this area. Establishment of our research team and the accomplishment of these goals will have high impact with regards to musculoskeletal disease. For example, sarcopenia and osteoporosis are serious health threats among the elderly and are the major causes for debilitating injuries, loss of independence, and reduced quality of life. The potential reciprocal consequences of muscle and bone diseases and how they influence overall health and disease during aging are not known. Therefore, this new line of research should have high impact, and may lead to the discovery of new factors that could be targets of therapeutic intervention for the prevention of bone and muscle diseases.