PARENT GRANT PROJECT SUMMARY 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 the University of Florida, College of Pharmacy and Engineering and AdventHealth Translational Research Institute. 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 non-existent in part because of an incomplete understanding of the mechanisms controlling age-related skeletal muscle dysfunction. Our team has developed a 2D 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 develop a microphysiological (MPS) 3D system and incorporate electrodes into the chip. We will determine electric field strength distribution using COMSOL modeling and optimize conditions for electrically stimulating muscle myocytes embedded in a native extracellular matrix. Our MPS will be integrated into a remote controlled, fully automated laboratory 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 the TangoLab experimental flight facility. On a subsequent flight, we propose to test natural products with anti-atrophy properties in the validated MPS. 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 MPS 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 to treat muscle wasting.