Increasing lean muscle mass in mice via nanoparticle-mediated hepatic delivery of follistatin mRNA

Canan Schumann, Duc X. Nguyen, Mason Norgard, Yulia Bortnyak, Tetiana Korzun, Stephanie Chan, Anna St Lorenz, Abraham S. Moses, Hassan A. Albarqi, Leon Wong, Katherine Michaelis, Xinxia Zhu, Adam W.G. Alani, Olena R. Taratula, Stephanie Krasnow, Daniel L. Marks, Oleh Taratula

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Muscle atrophy occurs during chronic diseases, resulting in diminished quality of life and compromised treatment outcomes. There is a high demand for therapeutics that increase muscle mass while abrogating the need for special dietary and exercise requirements. Therefore, we developed an efficient nanomedicine approach capable of increasing muscle mass. Methods: The therapy is based on nanoparticle-mediated delivery of follistatin messenger RNA (mRNA) to the liver after subcutaneous administration. The delivered mRNA directs hepatic cellular machinery to produce follistatin, a glycoprotein that increases lean mass through inhibition of negative regulators of muscle mass (myostatin and activin A). These factors are elevated in numerous disease states, thereby providing a target for therapeutic intervention. Results: Animal studies validated that mRNA-loaded nanoparticles enter systemic circulation following subcutaneous injection, accumulate and internalize in the liver, where the mRNA is translated into follistatin. Follistatin serum levels were elevated for 72 h post injection and efficiently reduced activin A and myostatin serum concentrations. After eight weeks of repeated injections, the lean mass of mice in the treatment group was ~10% higher when compared to that of the controls. Conclusion: Based on the obtained results demonstrating an increased muscle mass as well as restricted fat accumulation, this nanoplatform might be a milestone in the development of mRNA technologies and the treatment of muscle wasting disorders.

Original languageEnglish (US)
Pages (from-to)5276-5288
Number of pages13
JournalTheranostics
Volume8
Issue number19
DOIs
StatePublished - 2018

Keywords

  • Activin A
  • Follistatin
  • Muscle atrophy
  • Myostatin
  • Polymeric nanoparticles
  • mRNA

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Pharmacology, Toxicology and Pharmaceutics (miscellaneous)

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    Schumann, C., Nguyen, D. X., Norgard, M., Bortnyak, Y., Korzun, T., Chan, S., Lorenz, A. S., Moses, A. S., Albarqi, H. A., Wong, L., Michaelis, K., Zhu, X., Alani, A. W. G., Taratula, O. R., Krasnow, S., Marks, D. L., & Taratula, O. (2018). Increasing lean muscle mass in mice via nanoparticle-mediated hepatic delivery of follistatin mRNA. Theranostics, 8(19), 5276-5288. https://doi.org/10.7150/thno.27847