Chemotherapeutic drug screening in 3D-Bioengineered human myobundles provides insight into taxane-induced myotoxicities
Summary: 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 T...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-10-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004222014614 |
| _version_ | 1811182243691888640 |
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| author | Maria J. Torres Xu Zhang Dorothy H. Slentz Timothy R. Koves Hailee Patel George A. Truskey Deborah M. Muoio |
| author_facet | Maria J. Torres Xu Zhang Dorothy H. Slentz Timothy R. Koves Hailee Patel George A. Truskey Deborah M. Muoio |
| author_sort | Maria J. Torres |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-04-11T09:29:18Z |
| format | Article |
| id | doaj.art-c8925c5ae8554c5e8f3c1c0d1e770e8d |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-04-11T09:29:18Z |
| publishDate | 2022-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-c8925c5ae8554c5e8f3c1c0d1e770e8d2022-12-22T04:31:57ZengElsevieriScience2589-00422022-10-012510105189Chemotherapeutic drug screening in 3D-Bioengineered human myobundles provides insight into taxane-induced myotoxicitiesMaria J. Torres0Xu Zhang1Dorothy H. Slentz2Timothy R. Koves3Hailee Patel4George A. Truskey5Deborah M. Muoio6Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University, Durham, NC 27701, USADepartment of Biomedical Engineering, Duke University, Durham, NC 27708, USADuke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University, Durham, NC 27701, USADuke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University, Durham, NC 27701, USADepartment of Biomedical Engineering, Duke University, Durham, NC 27708, USADepartment of Biomedical Engineering, Duke University, Durham, NC 27708, USADuke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University, Durham, NC 27701, USA; Department of Medicine, Division of Endocrinology, Metabolism, and Nutrition, Duke University, Durham, NC 27708, USA; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27708, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2589004222014614PharmacologyBiological sciencesCancerBioengineering |
| spellingShingle | Maria J. Torres Xu Zhang Dorothy H. Slentz Timothy R. Koves Hailee Patel George A. Truskey Deborah M. Muoio Chemotherapeutic drug screening in 3D-Bioengineered human myobundles provides insight into taxane-induced myotoxicities iScience Pharmacology Biological sciences Cancer Bioengineering |
| title | Chemotherapeutic drug screening in 3D-Bioengineered human myobundles provides insight into taxane-induced myotoxicities |
| title_full | Chemotherapeutic drug screening in 3D-Bioengineered human myobundles provides insight into taxane-induced myotoxicities |
| title_fullStr | Chemotherapeutic drug screening in 3D-Bioengineered human myobundles provides insight into taxane-induced myotoxicities |
| title_full_unstemmed | Chemotherapeutic drug screening in 3D-Bioengineered human myobundles provides insight into taxane-induced myotoxicities |
| title_short | Chemotherapeutic drug screening in 3D-Bioengineered human myobundles provides insight into taxane-induced myotoxicities |
| title_sort | chemotherapeutic drug screening in 3d bioengineered human myobundles provides insight into taxane induced myotoxicities |
| topic | Pharmacology Biological sciences Cancer Bioengineering |
| url | http://www.sciencedirect.com/science/article/pii/S2589004222014614 |
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