This grant application, in response to RFA-TR-18-001 ?NIH-CASIS Coordinated Microphysiological Systems Program for Translational Research in Space?, proposes an outstanding collaborative effort among investigators at Sanford Burnham Prebys Medical Discovery Institute, SpacePharma, INC, Florida Hospital Translational Research Institute for Metabolism and Diabetes, the University of Florida Department of Biomedical Engineering and Space Technology and Advanced Research Systems (STaARS). Astronauts suffer from muscle degeneration after prolonged spaceflight. These effects are largely reversible; however, the intrinsic changes in skeletal muscle observed with age such as DNA damage, cellular stress, mitochondrial dysfunction and senescence are likely to overlap with cellular mechanisms induced in microgravity. Thus, studies in microgravity using human tissue to model disease conditions may greatly contribute to development of clinically relevant approaches to address muscle wasting in the elderly referred to as sarcopenia. The number of elderly individuals over the age of 60 is growing at an unprecedented rate from ~11% of the global population today to ~21% by 2050. Therapeutic options to treat sarcopenia are relatively non-existent in part because of an incomplete understanding of the mechanisms controlling age-related skeletal muscle dysfunction. Our team has been focused on developing a millifluidic lab-on-a-chip system to study human skeletal muscle cell growth and gene expression changes in microgravity. We have established culture conditions for primary human myocytes isolated from young, healthy and older, sedentary volunteers and have biological data indicating that the cells retain the phenotype of the donor tissue. Furthermore, we have fabricated a flight ready chip with multiple culture chambers. For this proposal, we plan to incorporate electrodes into the chip and determine electric field strength distribution by simulation to optimize conditions for electrically stimulating muscle myocytes embedded in a native mimicking extracellular matrix. Our lab-on-a- chip will be integrated into a remote controlled, fully automated laboratory solution complete with a fluid handling system, an optical detection system to record contraction, and a software platform for near real-time control of the experiment on the ISS housed in STaARS-1 experimental flight facility. On a subsequent flight, we propose to test natural products with anti-atrophy properties in the validated lab-on-a-chip system. Drug delivery to the muscle cultures will be facilitated via the addition of an administration port capable of delivering multiple drug dilutions. Our next generation lab-on-a-chip system stands to be a leader in miniaturized lab disease modeling to study pathophysiological changes in muscle tissue induced in microgravity intended to advance drug efficacy and toxicological testing of therapeutics to elevate the burden of muscle wasting.
Physiological changes resulting in the loss of muscle mass and strength, similar to aging, occur ~10 times faster in microgravity and understanding how to prevent the degenerative loss of skeletal muscle mass is an extremely important area of research, especially as the percentage of our older population continues to increase; roughly a 10 percent reduction in age-related muscle atrophy would save 1.1 billion in annual healthcare costs while improving quality of life. We propose to develop a ?Lab-on-a-chip? device to culture and electrically stimulate human primary muscle cells isolated from muscle of young and aged adults. The automated, remote-controlled device placed on the International Space Station will serve as an advanced human cell system for studying physiological changes induced in microgravity that mimic aging and for predictive drug and toxicology testing to aide in the development of therapeutics for muscle wasting.
