Contributions of skeletal muscle loading during rotator cuff maturation and healing

项目摘要/摘要 肩袖的健康依赖于袖带肌肉和肌腱通过肌腱与骨骼的功能性连接- 骨陷窝。末端将肌肉力量传递到骨骼，而骨骼的结构和功能 倾角取决于肌肉负荷。在出生时肌肉或神经损伤的情况下，吻合不能 在分娩时，由于牵引力引起的肩部肌肉功能不全，应正确形成。肌肉功能恢复 在青少年肌肉恢复过程中，可能会使末端容易因延迟而损伤和断裂 在出生后成熟的关键期内形成的雌蕊。PI最近已经表明了这一要求 用于在末端的生长和成熟过程中的肌肉负荷，以及为了适当的愈合 修复了肩袖。虽然可以理解，肌肉负荷是发育过程中所必需的 但是，目前还不存在诱导生长过程中受控肌肉活动的实验方法。一 控制肌肉激活的潜在方法是使用光遗传工具，这种工具通过 光激活。我们的实验室专注于确定干预措施，如调节肌肉力量， 促进末端的成熟和重塑。这项工作将对治疗 像肌肉停用这样的发育障碍，因为我们将开发出理解肌肉如何 激活影响末端的成熟，也影响青少年末端的适应 肌肉停止使用，恢复负荷。在我们的第一个目标中，我们的目标是开发一种光遗传小鼠模型，用于 新生儿肩部肌肉局部激活。利用转基因小鼠和重组，我们将 人通道视紫红质-2(HChR2)/YFP融合蛋白在骨骼肌中的特异性表达 用于骨骼肌暴露于蓝光(450-490 nm)后的激活。在我们的第二个目标中，我们将 停用后反应性肩袖肌肉恢复吻合部形态和机械功能 建立新生大鼠肌肉废用模型。这些发现将为未来提供强有力的初步数据 R01提案，将在肌肉的小动物模型中研究靶向肌肉刺激的作用 停用。这项研究符合NICHD的长期目标，旨在确保 在这种难以治疗的情况下，通过优化的康复方法实现青少年个体的独立性 人口。通过利用发育生物学、生物力学、工程学、 和康复，PI准备在生物医学领域建立一个强大的综合研究计划 工程学。

PROJECT SUMMARY/ABSTRACT Rotator cuff health relies on the functional attachment of cuff muscle and tendon to bone via the tendon- bone enthesis. The enthesis transmits muscle forces to the skeleton, and the structure and function of the enthesis is dependent on muscle loading. In the case of muscle or nerve injury at birth, the enthesis fails to properly form due to traction-induced muscle disuse of the shoulder at childbirth. Return of muscle function during muscle recovery in adolescents can predispose the enthesis to damage and rupture due to delayed enthesis formation during critical periods of postnatal maturation. The PI has recently shown the requirement for muscle loading during the growth and maturation of the enthesis, as well as for proper healing of the repaired rotator cuff. While it is understood that the muscle loading is required for the development of the enthesis, experimental approaches that induce controlled muscle activity during growth are non-existent. One potential way of controlling muscle activation is via the use of optogenetic tools, which control cell behavior via light-activation. Our laboratory is focused on identifying interventions, such as regulating muscle force, that promote the maturation and remodeling of the enthesis. This work will have implications for treating developmental disorders like muscle disuse, as we will develop approaches for understanding how muscle activation influences the maturation of the enthesis as well as how the adolescent enthesis adapts following muscle disuse and return to loading. In our first aim, we aim to develop an optogenetic mouse model for the localized activation of neonatal shoulder muscles. Using transgenic mice and cre-recombination, we will develop and validate a skeletal muscle-specific expression of channelrhodopsin-2 (hChR2)/YFP fusion protein for the activation of skeletal muscle following exposure to blue light (450-490nm). In our second aim, we will reactive rotator cuff muscles following disuse to regain enthesis morphology and mechanical function in an established model of neonatal muscle disuse. These findings will provide strong preliminary data for a future R01 proposal that will investigate the role of targeted muscle stimulation in a small animal model of muscle disuse. This research fits within the long-term goals of NICHD by aiming to ensure the health, well-being, and independence of adolescent individuals through optimized rehabilitation approaches in this difficult-to-treat population. By utilizing multidisciplinary approaches from developmental biology, biomechanics, engineering, and rehabilitation, the PI is poised to establish a strong and integrative research program in biomedical engineering.