Microgravity is a unique environment for studying biological processes that could uncover important insights for drug discovery and development. In recent years, there have been significant efforts invested in building a research facility on the space station, with tools and hardware comparable to modern labs on Earth. Elevating research capabilities in space helps support and drive biomedical research endeavors that benefit society, including the development of drugs and therapies. Indeed, research performed in microgravity has already aided the FDA approval and marketing of several drugs.

Atrophy is a process that involves the breakdown and loss of tissue, which limits its functional capacity. Aging is a prime example of progressive tissue degeneration, whereby muscle mass declines up to 2% a year after the age of 50, while bone loss occurs at an average rate of 3-5% per decade. Other conditions such as disease, injury, and disuse, are factors that can also lead to various degrees of tissue atrophy. Interventions that can slow or reverse tissue loss and preserve function would be a boon to promoting healthy aging and for the treatment of degenerative diseases. In microgravity, muscle and bone experience measurable atrophy in a relatively short time span. The acceleration of disease phenotypes in animal models renders space a unique and powerful environment to test novel drugs for the purpose of preventing and/or reversing muscle and bone loss.

Myostatin 

Myostatin is a muscle secreted factor that negatively regulates muscle cell growth. Genetically engineered mice with disrupted myostatin function have significantly more muscle mass on Earth and are known as ‘mighty mice’. In space, these mutant mice were able to maintain their preflight muscle mass. In parallel, an antibody-based drug that acts to disrupt myostatin activity is currently in development as a countermeasure for muscle atrophy. In space, mice treated with a myostatin-antibody (YN41) prevented many space-induced muscle changes. Drugs targeting myostatin and its downstream effectors as therapies for muscle wasting disorders are in development, at various stages of clinical trials, by several pharmaceutical companies. 

Activin type IIB receptor decoy

Researchers from the University of Connecticut and Jackson Laboratory are developing a novel antibody-based drug to promote the growth and homeostasis of both muscle and bone. This drug (ACVR2B/Fc) is a fusion of the ligand-binding domain of activin type IIB receptor (ACVR2B) and an immunoglobulin Fc domain that acts as a receptor decoy, sequestering the ligands myostatin and activin A. This neutralizes ligands limiting the activation of downstream endogenous receptors. Compared to drugs that target myostatin alone, this ACVR2B/Fc drug broadens the specificity of ligand binding by including activin A, thereby affecting various tissues with the potential of addressing multiple disease states. 

Treatment with the ACVR2B/Fc drug led to dramatic increases in muscle and bone mass in microgravity, thereby protecting these tissues against atrophy while in space. Wildtype mice exposed to microgravity for 33 days experienced a 9% decrease in lean body mass, a measure that includes muscle mass, and reduced whole-body bone mineral density by 8%. Treatment of mice while in spaceflight with the AcVR2B/Fc decoy receptor, every 5-6 days, led to a 27% increase in lean body mass and a 4% increase in whole-body bone mineral density compared to untreated controls. 

In addition to the use of the drug as a preventive measure, the ACVR2B/Fc drug was able to reverse atrophied bone and muscle. Untreated mice sent to space for 33 days returned to Earth with significant muscle and bone loss. Two doses of the receptor-decoy drug enhanced recovery of lean muscle mass by almost three-fold compared to untreated mice. Treatment also led to the rebuilding of bone, such that bone mineral density recovered half of the density that was lost during spaceflight, while untreated controls failed to show any improvement. 

Overall, the microgravity environment led to the demonstration of the efficacy of the ACVR2B/Fc drug. Treatment with the drug prevented bone and muscle atrophy normally induced by microgravity and promoted the recovery of atrophied tissues following spaceflight. Further development of this drug in clinical trials may offer a novel treatment option for debilitating bone and muscle atrophy caused by aging, injury, disuse, or disease.

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Smith RC, Cramer MS, Mitchell PJ, Lucchesi J, Ortega AM, Livingston EW, Ballard D, Zhang L, Hanson J, Barton K, Berens S, Credille KM, Bateman TA, Ferguson VL, Ma YL, Stodieck LS. Inhibition of myostatin prevents microgravity-induced loss of skeletal muscle mass and strength. PLoS One. 2020;15(4):e0230818. doi: 10.1371/journal.pone.0230818. 

Lee SJ, Lehar A, Meir JU, Koch C, Morgan A, Warren LE, Rydzik R, Youngstrom DW, Chandok H, George J, Gogain J, Michaud M, Stoklasek TA, Liu Y, Germain-Lee EL. Targeting myostatin/activin A protects against skeletal muscle and bone loss during spaceflight. Proc Natl Acad Sci U S A. 2020;117(38):23942-51. doi: 10.1073/pnas.2014716117.