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

Maria J Torres; Xu Zhang; Dorothy H Slentz; Timothy R Koves; Hailee Patel; George A Truskey; Deborah M Muoio

doi:10.1016/j.isci.2022.105189

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

iScience. 2022 Sep 28;25(10):105189. doi: 10.1016/j.isci.2022.105189. eCollection 2022 Oct 21.

Authors

Maria J Torres¹, Xu Zhang², Dorothy H Slentz¹, Timothy R Koves¹, Hailee Patel², George A Truskey², Deborah M Muoio^{1

3

4}

Affiliations

¹ Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University, Durham, NC 27701, USA.
² Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA.
³ Department of Medicine, Division of Endocrinology, Metabolism, and Nutrition, Duke University, Durham, NC 27708, USA.
⁴ Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27708, USA.

Abstract

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.

Keywords: Bioengineering; Biological sciences; Cancer; Pharmacology.