Modeling the Effect of TNF-α upon Drug-Induced Toxicity in Human, Tissue-Engineered Myobundles
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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.
KeywordsTissue engineering Human skeletal muscle Inflammation TNF-α Drug testing Muscle regeneration
We gratefully acknowledge Chris Jackman and Alastair Khodabukus for excellent technical discussions; Megan Kondash for cell isolation; Ringo Yen for project support. This study was supported by NIH Grants UH2TR000505, 4UH3TR000505, UG3TR002142, from NCATS and NIAMS to GAT, as well as an NSF Graduate Research Fellowship to BNJD.
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