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

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.