Chemotherapeutic drug screening in 3D-Bioengineered human myobundles provides insight into taxane-induced myotoxicities.

Journal Article (Journal Article)

Two prominent frontline breast cancer (BC) chemotherapies commonly used in combination, doxorubicin (DOX) and docetaxel (TAX), are associated with long-lasting cardiometabolic and musculoskeletal side effects. Whereas DOX has been linked to mitochondrial dysfunction, mechanisms underlying TAX-induced myotoxicities remain uncertain. Here, the metabolic and functional consequences of TAX ± DOX were investigated using a 3D-bioengineered model of adult human muscle and a drug dosing regimen designed to resemble in vivo pharmacokinetics. DOX potently reduced mitochondrial respiratory capacity, 3D-myobundle size, and contractile force, whereas TAX-induced acetylation and remodeling of the microtubule network led to perturbations in glucose uptake, mitochondrial respiratory sensitivity, and kinetics of fatigue, without compromising tetanic force generation. These findings suggest TAX-induced remodeling of the microtubule network disrupts glucose transport and respiratory control in skeletal muscle and thereby have important clinical implications related to the cardiometabolic health and quality of life of BC patients and survivors.

Full Text

Duke Authors

Cited Authors

  • Torres, MJ; Zhang, X; Slentz, DH; Koves, TR; Patel, H; Truskey, GA; Muoio, DM

Published Date

  • October 21, 2022

Published In

Volume / Issue

  • 25 / 10

Start / End Page

  • 105189 -

PubMed ID

  • 36274957

Pubmed Central ID

  • PMC9579017

Electronic International Standard Serial Number (EISSN)

  • 2589-0042

Digital Object Identifier (DOI)

  • 10.1016/j.isci.2022.105189

Language

  • eng

Conference Location

  • United States