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

身体虚弱会影响老年人保持独立的能力，这主要是由于与年龄相关的骨骼肌质量损失（肌肉减少症）造成的。肌肉减少症会导致行动能力丧失、残疾和依赖性增加，以及跌倒风险增加，这可能是致命的。在美国，与肌肉减少症相关的残疾相关的医院费用估计为每年 404 亿美元。尽管个人和社会成本巨大，但尚未找到广泛适用的预防与年龄相关的肌肉损失的治疗方法，并且在理解其背后的机制方面仅取得了有限的进展。这种缺乏了解是开发最佳疗法以减轻虚弱严重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，并且有可能用于加速肌肉减少症治疗方法的发现。因此，微重力提供了一个独特的实验环境，可以在失重、无负载的状态下测试生理系统，这可能会对肌肉减少症与年龄相关的病理生理学产生新的见解，从而确定干预的关键点。 NSF/CASIS 在国际空间站 (ISS) 上的组织工程和机械生物学合作以造福地球生命奖支持在这一独特环境中的研究。鉴于美国普通民众对身体和精神上的脆弱性知之甚少，该项目还旨在与利益相关者合作，改善老年人的环境（例如技术开发制造商、医疗保健工作者、公众、老年患者群体）。肌肉减少症的特点是神经肌肉接头结构破坏和肌肉处理活性氧 (ROS) 能力的变化。神经肌肉接头结构的破坏也因微重力而加速。总体假设是，微重力和衰老会导致神经肌肉接头结构和功能的类似破坏，从而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，该生物反应器可用于国际空间站（ISS）和地面实验。这些结果，即实时评估的力的产生和ROS的产生，将通过对神经肌肉接头结构、转录谱和分泌因子的后续分析得到增强，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，从而有可能开发出针对这两种情况的新型干预措施。这种生物反应器的能力对学术研究人员来说非常有吸引力，特别是作为啮齿动物研究的可行替代方案。新型生物反应器系统将提供快速测试药物或非药物干预措施的资源，以维持老年人的神经肌肉功能、肌肉质量和虚弱以及其他关键的临床疾病，因此将吸引工业合作伙伴。老年人口与年龄相关的肌肉无力的发病率显着增加，这需要增加对抗衰老产品和生活方式干预措施的需求，这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，并通过使用基金会的智力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.