A multiplexed in vitro assay system for evaluating human skeletal muscle functionality in response to drug treatment

• Published in: Biotechnology and bioengineering 2020-03, Vol.117 (3), p.736-747
• Main Authors: Najjar, Sarah A., Smith, Alexander S.T., Long, Christopher J., McAleer, Christopher W., Cai, Yunqing, Srinivasan, Balaji, Martin, Candace, Vandenburgh, Herman H., Hickman, James J.
• Format: Article
• Language: English
• Subjects: Atorvastatin - toxicity; body‐on‐a‐chip; cantilevers; Cells, Cultured; Data collection; Doxorubicin - toxicity; Drug development; Drug Evaluation, Preclinical - methods; Electrical stimuli; functional assay; human; Human performance; Humans; Induced Pluripotent Stem Cells - drug effects; Lab-On-A-Chip Devices; Models, Biological; Muscle contraction; Muscle Contraction - drug effects; Muscle Fibers, Skeletal - cytology; Muscle Fibers, Skeletal - drug effects; Muscle, Skeletal - cytology; Muscle, Skeletal - drug effects; Muscle, Skeletal - physiology; Muscles; Muscular Dystrophies - metabolism; Muscular fatigue; Musculoskeletal system; Myotubes; Physiological responses; Screening; Skeletal muscle
• ISSN: 0006-3592; 1097-0290
• DOI: 10.1002/bit.27231

In vitro systems that mimic organ functionality have become increasingly important tools in drug development studies. Systems that measure the functional properties of skeletal muscle are beneficial to compound screening studies and also for integration into multiorgan devices. To date, no studies have investigated human skeletal muscle responses to drug treatments at the single myotube level in vitro. This report details a microscale cantilever chip‐based assay system for culturing individual human myotubes. The cantilevers, along with a laser and photo‐detector system, enable measurement of myotube contractions in response to broad‐field electrical stimulation. This system was used to obtain baseline functional parameters for untreated human myotubes, including peak contractile force and time‐to‐fatigue data. The cultured myotubes were then treated with known myotoxic compounds and the resulting functional changes were compared to baseline measurements as well as known physiological responses in vivo. The collected data demonstrate the system's capacity for screening direct effects of compound action on individual human skeletal myotubes in a reliable, reproducible, and noninvasive manner. Furthermore, it has the potential to be utilized for high‐content screening, disease modeling, and exercise studies of human skeletal muscle performance utilizing iPSCs derived from specific patient populations such as the muscular dystrophies. In vitro systems that mimic organ functionality are important for drug development studies. The authors developed and validated a systems for measuring the functional properties of human skeletal muscle at the single myotube level in vitro. This cantilever chip‐based system can be used for compound screening studies and integrated into multiorgan devices.