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，主要是由于年龄相关的骨骼肌质量损失（肌肉减少症）。肌肉减少症导致丧失活动能力和增加残疾和依赖性，以及增加福尔斯跌倒的风险，这可能是致命的。在美国，与肌肉减少症残疾相关的估计医院费用为每年404亿美元。尽管有巨大的个人和社会成本，没有广泛适用的治疗方法来防止与年龄相关的肌肉损失已经确定，只有适度的进展，在了解其背后的机制。这种缺乏了解是一个关键的障碍，开发最佳的治疗方法，以减少脆弱的严重性及其破坏性的影响。宇航员和动物暴露在微重力环境下会经历类似的肌肉质量和功能损失，这表明微重力是研究与年龄相关的肌肉功能损失的加速模型，并可能用于加速发现肌肉减少症的治疗方法。因此，微重力提供了一个独特的实验环境，以测试生理系统在失重，卸载，状态，可能会导致新的见解与年龄相关的肌肉减少症的病理生理学，允许识别干预的关键点。NSF/CASIS在国际空间站（ISS）上组织工程和机械生物学合作，以造福地球上的生命奖支持在这种独特环境中的研究。鉴于美国普通民众对身体和精神脆弱的理解不足，该项目还旨在与利益攸关方合作，改善老年人的环境（例如，技术开发制造商、卫生保健工作者、普通公众、老年患者群体）。肌肉减少症的特征在于神经肌肉接头结构的破坏和肌肉处理活性氧（ROS）的能力的变化。神经肌肉接头结构的破坏也被认为是对微重力的加速反应。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受到类似的破坏，从而导致神经-肌肉相互作用，导致肌肉质量和功能丧失。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，收缩和监测来自组织工程人类神经肌肉结构的收缩诱导的活性氧，该结构可用于国际空间站（ISS）和地面实验。这些结果，力的产生和ROS的产生，在真实的时间进行评估，将通过随后的神经肌肉接头结构，转录谱和分泌因子的分析来增强，这些分析将为衰老和微重力环境中的肌肉无力提供重要的见解，从而为这两种情况开发新的干预措施。这种生物反应器的能力将对学术研究人员非常有吸引力，特别是作为使用啮齿动物进行研究的可行替代方案。新型生物反应器系统将提供一种资源，用于快速测试药物或非药物干预措施，以维持老年人和其他关键临床疾病的神经肌肉功能和肌肉质量和虚弱，因此将吸引工业合作伙伴。随着年龄相关性肌无力发病率的增加，对抗肌无力药物的需求增加。抗衰老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，由于其发展，有可能带来经济效益和改善生活质量。该奖项反映了NSF的法定使命，并被认为值得支持通过使用基金会的知识价值和更广泛的影响审查标准进行评估。

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.