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


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.





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Publication Info

Torres, Maria J, Xu Zhang, Dorothy H Slentz, Timothy R Koves, Hailee Patel, George A Truskey and Deborah M Muoio (2022). Chemotherapeutic drug screening in 3D-Bioengineered human myobundles provides insight into taxane-induced myotoxicities. iScience, 25(10). p. 105189. 10.1016/j.isci.2022.105189 Retrieved from

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Timothy Robert Koves

Associate Professor in Medicine

My research is focused on 1) understanding metabolic perturbations that occur in subpopulations of skeletal muscle mitochondria in response to a chronic high lipid environment, 2) identifying specific metabolites of lipid-induced mitochondrial stress that contribute to skeletal muscle insulin resistance and type II diabetes, and 3) understanding how mitochondrial adaptations in response to exercise confer protection against lipid-induced mitochondrial dysfunction.


George A. Truskey

R. Eugene and Susie E. Goodson Distinguished Professor of Biomedical Engineering

My research interests focus upon the effect of physical forces on the function of vascular cells and skeletal muscle, cell adhesion, and the design of engineered tissues.  Current research projects examine the  effect of endothelial cell senescence upon permeability to macromolecules and the response to fluid shear stress, the development of microphysiological blood vessels and muscles for evaluation of drug toxicity and the design of engineered endothelialized blood vessels and skeletal muscle bundles.


Deborah Marie Muoio

George Barth Geller Distinguished Professor of Cardiovascular Disease

Deb Muoio is professor in the Departments of Medicine and Pharmacology & Cancer Biology, George Barth Geller Distinguished Professor of Cardiovascular Disease, and Associate Director of the Duke Molecular Physiology Institute (DMPI). She is viewed nationally and internationally as a leader in the fields of diabetes, obesity, exercise physiology, and mitochondrial energy metabolism. Her laboratory investigates mechanisms of metabolic regulation, with emphasis on molecular events that link lifestyle factors such as over nutrition and physical inactivity to metabolic disorders, including obesity, diabetes, and heart failure. Her program features a translational approach that combines work in animal and cell-based models with human studies, using genetic engineering, molecular biology and mass spectrometry-based metabolomics and proteomics as tools to understand the interplay between mitochondrial physiology and cardiometabolic health. Her laboratory developed a sophisticated platform for deep and comprehensive assessment of mitochondrial bioenergetics and energy transduction. Her team is integrating this new platform with metabolomics, proteomics, and metabolic flux analysis to gain insights into mechanisms by which mitochondria modulate insulin action and metabolic resilience. She has published more than 120 papers in prominent journals such as Cell, Cell Metabolism, Circulation, Circulation Research, Diabetes, and JCI Insight. Dr. Muoio’s laboratory has enjoyed longstanding support from the NIDDK and NHLBI.

PhD, University of North Carolina, Chapel Hill, NC

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