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质量损失（肌肉减少症）。骨骼肌减少症导致行动能力丧失，残疾和依赖性增加，以及摔倒的风险增加，这可能是致命的。在美国，与肌肉减少症相关的医院费用估计每年为404亿美元。尽管付出了巨大的个人和社会代价，但目前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，而且在了解其背后的机制方面也只取得了有限的进展。这种缺乏理解是开发最佳治疗方法以减少虚弱的严重程度及其破坏性影响的关键障碍。暴露在微重力环境下的宇航员和动物也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，可能被用来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来测试失重状态下的生理系统，这可能会对肌肉减少症的年龄相关病理生理产生新的见解，从而确定干预的关键点。美国国家科学基金会/中国科学院国际空间站（ISS）组织工程和力学生物学合作造福地球生命奖支持在这种独特环境下的研究。鉴于美国普通民众对身体和精神脆弱性的了解不足，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）。肌肉减少症的特征是神经肌肉连接结构的破坏和肌肉处理活性氧（ROS）能力的变化。在微重力作用下，神经肌肉连接结构的破坏也以加速的方式出现。总的假设是，微重力和衰老导致神经肌肉连接的结构和功能类似的破坏，因此神经肌肉相互作用导致肌肉质量和功能的损失。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活性氧，该生物反应器可用于国际空间站（ISS）和地面实验。通过对神经肌肉连接结构、转录谱和分泌因子的后续分析，实时评估这些结果（力产生和ROS产生）将得到增强，这将为衰老和微重力环境下的肌肉无力提供重要的见解，从而为这两种情况带来新的干预措施的潜在发展。这种生物反应器的能力将对学术研究人员非常有吸引力，特别是作为啮齿动物研究的可行替代方案。这种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、肌肉质量和虚弱，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生率显著增加，对抗衰老产品和生活方式干预的需求增加，这对制药和个人护理产品部门具有巨大的经济潜力，因此它们的发展有可能带来经济效益和改善生活质量。该奖项反映了美国国家科学基金会的法定使命，并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，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.