Human, Tissue-Engineered, Skeletal Muscle Myobundles to Measure Oxygen Uptake and Assess Mitochondrial Toxicity.

Journal Article

Mitochondrial dysfunction is responsible for the toxicity of a number of drugs. Current isolated mitochondria or cellular monoculture mitochondrial respiration measurement systems lack physiological relevance. Using a tissue engineering rather than cell- or mitochondria-based approach enables a more physiologically relevant detection of drug-induced mitochondrial impairment. To probe oxygen consumption and mitochondrial health, we assayed the bioenergetic profile of engineered three-dimensional human skeletal muscle myobundles derived from primary myoblasts. Through experimental and computational techniques, we did not find external or internal oxygen transport limiting the engineered myobundles in the commercial O2k system to measure oxygen consumption. In response to the complex I inhibitor rotenone, myobundle basal respiration decreased dose dependently with an IC50 of 9.24 ± 0.03 nM. At a 20 nM concentration of rotenone, myobundle maximal respiration decreased by 44.4% ± 9.8%. Respiratory depression by rotenone suggests that cultured myobundles rely heavily on the complex I pathway for ATP synthesis during times of both basal and increased energy demand. To address whether these decrements in mitochondrial function corresponded to alterations in physiological muscle function, we determined fatigue susceptibility that revealed a 46.0% ± 7.4% depression at 20 nM rotenone. The bioenergetic health index, which is a measure of normal oxidative mitochondrial function, was inversely correlated with the extent of fatigue. The human myobundles reproduce normal muscle metabolism under both basal and maximal energy demand conditions enabling the detection of drug-induced mitochondrial toxicity.

Full Text

Duke Authors

Cited Authors

  • Davis, BNJ; Santoso, JW; Walker, MJ; Cheng, CS; Koves, TR; Kraus, WE; Truskey, GA

Published Date

  • April 2017

Published In

Volume / Issue

  • 23 / 4

Start / End Page

  • 189 - 199

PubMed ID

  • 28338413

Electronic International Standard Serial Number (EISSN)

  • 1937-3392

International Standard Serial Number (ISSN)

  • 1937-3384

Digital Object Identifier (DOI)

  • 10.1089/ten.tec.2016.0264

Language

  • eng