Modeling the Effect of TNF-α upon Drug-Induced Toxicity in Human, Tissue-Engineered Myobundles.

Published

Journal Article

A number of significant muscle diseases, such as cachexia, sarcopenia, systemic chronic inflammation, along with inflammatory myopathies share TNF-α-dominated inflammation in their pathogenesis. In addition, inflammatory episodes may increase susceptibility to drug toxicity. To assess the effect of TNF-α-induced inflammation on drug responses, we engineered 3D, human skeletal myobundles, chronically exposed them to TNF-α during maturation, and measured the combined response of TNF-α and the chemotherapeutic doxorubicin on muscle function. First, the myobundle inflammatory environment was characterized by assessing the effects of TNF-α on 2D human skeletal muscle cultures and 3D human myobundles. High doses of TNF-α inhibited maturation in human 2D cultures and maturation and function in 3D myobundles. Then, a tetanus force dose-response curve was constructed to characterize doxorubicin's effects on function alone. The combination of TNF-α and 10 nM doxorubicin exhibited a synergistic effect on both twitch and tetanus force production. Overall, the results demonstrated that inflammation of a 3D, human skeletal muscle inflammatory system alters the response to doxorubicin.

Full Text

Duke Authors

Cited Authors

  • Davis, BNJ; Santoso, JW; Walker, MJ; Oliver, CE; Cunningham, MM; Boehm, CA; Dawes, D; Lasater, SL; Huffman, K; Kraus, WE; Truskey, GA

Published Date

  • April 8, 2019

Published In

PubMed ID

  • 30963383

Pubmed Central ID

  • 30963383

Electronic International Standard Serial Number (EISSN)

  • 1573-9686

International Standard Serial Number (ISSN)

  • 0090-6964

Digital Object Identifier (DOI)

  • 10.1007/s10439-019-02263-8

Language

  • eng