Bioengineered human myobundles mimic clinical responses of skeletal muscle to drugs.
Abstract
Existing in vitro models of human skeletal muscle cannot recapitulate the organization
and function of native muscle, limiting their use in physiological and pharmacological
studies. Here, we demonstrate engineering of electrically and chemically responsive,
contractile human muscle tissues ('myobundles') using primary myogenic cells. These
biomimetic constructs exhibit aligned architecture, multinucleated and striated myofibers,
and a Pax7(+) cell pool. They contract spontaneously and respond to electrical stimuli
with twitch and tetanic contractions. Positive correlation between contractile force
and GCaMP6-reported calcium responses enables non-invasive tracking of myobundle function
and drug response. During culture, myobundles maintain functional acetylcholine receptors
and structurally and functionally mature, evidenced by increased myofiber diameter
and improved calcium handling and contractile strength. In response to diversely acting
drugs, myobundles undergo dose-dependent hypertrophy or toxic myopathy similar to
clinical outcomes. Human myobundles provide an enabling platform for predictive drug
and toxicology screening and development of novel therapeutics for muscle-related
disorders.
Type
Journal articleSubject
contractile forcedrug testing
human
human biology
human skeletal muscle
medicine
muscle physiology
tissue engineering
Acetylcholine
Bioengineering
Biomechanical Phenomena
Caffeine
Calcium
Calcium Signaling
Genes, Reporter
Humans
Muscle Contraction
Muscle, Skeletal
Reproducibility of Results
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https://hdl.handle.net/10161/9364Published Version (Please cite this version)
10.7554/eLife.04885Publication Info
Madden, Lauran; Juhas, Mark; Kraus, William E; Truskey, George A; & Bursac, Nenad (2015). Bioengineered human myobundles mimic clinical responses of skeletal muscle to drugs.
Elife, 4. pp. e04885. 10.7554/eLife.04885. Retrieved from https://hdl.handle.net/10161/9364.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Nenad Bursac
Professor of Biomedical Engineering
Bursac's research interests include: Stem cell, tissue engineering, and gene based
therapies for heart and muscle regeneration; Cardiac electrophysiology and arrhythmias;
Organ-on-chip and tissue engineering technologies for disease modeling and therapeutic
screening; Small and large animal models of heart and muscle injury, disease, and
regeneration.
The focus of my research is on application of pluripotent stem cells, tissue engineering,
and gene therapy technologies for: 1) basic s
William Erle Kraus
Richard and Pat Johnson University Distinguished Professor
My training, expertise and research interests range from human integrative physiology
and genetics to animal exercise models to cell culture models of skeletal muscle adaptation
to mechanical stretch. I am trained clinically as an internist and preventive cardiologist,
with particular expertise in preventive cardiology and cardiac rehabilitation. My
research training spans molecular biology and cell culture, molecular genetics, and
integrative human exercise physiology and metabolism. I pr
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 skelet
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