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Ann Biomed Eng. 2019 Jul;47(7):1596-1610. doi: 10.1007/s10439-019-02263-8. Epub 2019 Apr 8.

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

Author information

1
Department of Biomedical Engineering, Duke University, Durham, NC, 27705, USA.
2
Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
3
Department of Textile Technology, RWTH Aachen University, 52062, Aachen, Germany.
4
Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, 27701, USA.
5
Department of Medicine, Duke University Medical Center, Durham, NC, 27710, USA.
6
Department of Cardiology, Duke University Medical Center, Durham, NC, 27710, USA.
7
Department of Biomedical Engineering, Duke University, Durham, NC, 27705, USA. george.truskey@duke.edu.
8
, 1395 FCIEMS, 101 Science Drive, Durham, NC, 27708-0281, USA. george.truskey@duke.edu.

Abstract

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.

KEYWORDS:

Drug testing; Human skeletal muscle; Inflammation; Muscle regeneration; TNF-α; Tissue engineering

PMID:
30963383
PMCID:
PMC6559943
[Available on 2020-07-01]
DOI:
10.1007/s10439-019-02263-8

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