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

ABSTRACT: A number of significant muscle diseases, such as cachexia, sarcopenia, systemic chronic inflammation, along with inflammatory myopathies share TNF-?-dominated inflammation in their pathogenesis. In addition, inflammatory episodes may increase susceptibility to drug toxicity. To assess the effect of TNF-?-induced inflammation on drug responses, we engineered 3D, human skeletal myobundles, chronically exposed them to TNF-? during maturation, and measured the combined response of TNF-? and the chemotherapeutic doxorubicin on muscle function. First, the myobundle inflammatory environment was characterized by assessing the effects of TNF-? on 2D human skeletal muscle cultures and 3D human myobundles. High doses of TNF-? 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-? 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.

SUBMITTER: Davis BNJ 

PROVIDER: S-EPMC6559943 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature