ISS: Accelerated disruption of the neuromuscular junction (NMJ) in microgravity: a model for muscle aging

身体虚弱影响老年人保持独立的能力，主要是由于与年龄相关的骨骼肌块的减少(骨质疏松症)。骨质疏松症会导致行动不便、残疾和依赖性增加，并增加跌倒的风险，这可能是致命的。据估计，在美国，每年与石棺生成障碍相关的医院费用为404亿美元。尽管付出了巨大的个人和社会代价，但还没有找到广泛适用的治疗方法来预防与年龄相关的肌肉损失，在了解其背后的机制方面也只取得了一定的进展。这种缺乏理解是开发最佳治疗方法以降低脆弱程度及其破坏性影响的关键障碍。暴露在微重力下的宇航员和动物会经历类似的肌肉质量和功能丧失，这表明微重力是研究与年龄相关的肌肉功能丧失的加速模型，可能会被用来加速发现治疗石棺减少的方法。因此，微重力提供了一个独特的实验环境，在失重、卸载的状态下测试生理系统，这可能会导致对与年龄相关的石棺减少的病理生理学的新见解，从而识别干预的关键点。NSF/CASIS在国际空间站(ISS)组织工程和机械生物学方面的合作，以造福地球上的生命，支持在这一独特环境中的研究。鉴于普通美国人对身体和精神上的脆弱都缺乏了解，该项目还旨在与利益相关者合作，为老年人(例如，技术开发制造商、卫生保健工作者、普通公众、老年患者队列)改善环境。萨科普减少症的特点是神经肌肉连接结构的破坏和肌肉处理活性氧物种(ROS)的能力变化。神经肌肉连接结构的破坏也以一种加速的方式出现，以响应微重力。总的假设是，微重力和衰老导致神经肌肉接头的结构和功能类似的破坏，从而神经-肌肉相互作用导致肌肉质量和功能的丧失。为了解决这一假设，将开发一种完全集成的生物反应器，用于长期培养、收缩和监测收缩诱导的组织工程化人类神经肌肉结构中的活性氧物种，该结构可用于国际空间站(ISS)和地面实验。这些结果、力量产生和ROS产生，将通过随后对神经肌肉连接结构、转录图谱和分泌因子的分析得到增强，这些因素将为衰老和微重力环境中的肌肉无力提供重要的见解，导致针对这两种情况的新干预措施的潜在开发。这种生物反应器的能力将非常吸引学术研究人员，特别是作为使用啮齿动物进行研究的可行替代方案。这种新型的生物反应器系统将提供一种资源，以快速测试药物或非药物干预措施，以维持神经肌肉功能和肌肉质量，以及老年人和其他关键临床疾病的虚弱，因此将吸引工业合作伙伴。随着老年人口的增加，与年龄相关的肌肉无力的发病率显著增加，对抗衰老产品和生活方式干预的需求增加，这些产品和生活方式干预对制药和个人护理产品行业具有巨大的经济潜力，因此它们的发展具有经济效益和改善生活质量的潜力。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Physical frailty affects the ability of older people to remain independent and is mainly due to the age-related loss of skeletal muscle mass (sarcopenia). Sarcopenia causes loss of mobility and increased disability and dependency, as well as increased risk of falls, which can be fatal. The estimated hospital cost associated with sarcopenic disabilities in the United States is $40.4 billion per year. Despite the huge personal and societal costs, no broadly applicable treatments to prevent age-related muscle loss have been identified and only modest progress has been made in understanding the mechanisms behind it. This lack of understanding is a critical barrier to developing optimal therapies to reduce the severity of frailty and its devastating effects. Astronauts and animals exposed to microgravity experience similar loss of muscle mass and function, suggesting that microgravity is an accelerated model for studying age-associated loss of muscle function and could potentially be used to accelerate the discovery of treatments for sarcopenia. Therefore, microgravity offers a unique experimental environment to test physiological systems in a weightless, unloaded, state that may lead to new insights into the age-associated pathophysiology of sarcopenia allowing for identification of key points for intervention. This NSF/CASIS Collaboration on Tissue Engineering and Mechanobiology on the International Space Station (ISS) to Benefit Life on Earth award supports research in this unique environment. Given the poor understanding of frailty, both physical and mental frailty, by the general USA populations, the project also aims to engage with stakeholders to improve the environment for older people (e.g., technology development manufacturers, health care workers, general public, aging patient cohorts).Sarcopenia is marked by a disruption of the structure of neuromuscular junctions and changes in the ability of muscles to handle reactive oxygen species (ROS). Disruption of the neuromuscular junction structure is also seen in an accelerated way in response to microgravity. The overall hypothesis is that microgravity and aging result in similar disruptions of the structure and function of neuromuscular junctions and thus nerve-muscle interactions leading to loss of muscle mass and function. To address this hypothesis, a fully integrated bioreactor for long-term culture, contraction and monitoring of contraction-induced reactive oxygen species from tissue-engineered human nerve-muscle constructs that can be used both on the International Space Station (ISS) and ground experiments will be developed. These outcomes, force generation and ROS generation, evaluated in real time, will be augmented by subsequent analysis of neuromuscular junction structure, transcriptional profiles, and secreted factors that will provide important insights into muscle weakness in aging and microgravity environments, leading to the potential development of novel interventions for both situations. This bioreactor capability will be very attractive to academic researchers, especially as a viable alternative to studies using rodents. The novel bioreactor system will provide a resource to rapidly test pharmaceutical or non-pharmaceutical interventions to maintain neuromuscular function and muscle mass and weakness in the elderly and other key clinical disorders and so will be appealing to industrial partners. An increasing elderly population with significant incidence of age-associated muscle weakness requires an increased demand for anti-aging products and lifestyle interventions which have enormous economic potential for the pharmaceutical and personal care products sector and there is therefore potential for economic benefit and improved quality of life as a result of their development.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.