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.
Highlights
Development of human in vitro systems for basic biological studies and drug discovery is motivated by the need to improve outcomes in human patients and alleviate ethical considerations demanding a reduction in the use of animals (Dambach and Uppal, 2012; Bhatia and Ingber, 2014)
The need for an accurate preclinical model of human skeletal muscle was exemplified by the market withdrawal of cerivastatin that was well tolerated in mice but caused fatal rhabdomyolysis in humans
Myogenic cells were isolated from human muscle biopsies and expanded for 3–5 passages, when they contained a significant fraction of muscle precursors positive for desmin and MyoD (Figure 1—figure supplement 1)
Summary
Development of human in vitro systems for basic biological studies and drug discovery is motivated by the need to improve outcomes in human patients and alleviate ethical considerations demanding a reduction in the use of animals (Dambach and Uppal, 2012; Bhatia and Ingber, 2014). While significant progress has been made towards predictive in vitro models for liver, lung, and cardiac tissues (Bhatia and Ingber, 2014), a functional model of human skeletal muscle has not been described. This is of particular concern as there are a wide range of metabolic, neuromuscular, and dystrophic disorders involving skeletal muscle that are under investigation and still lacking therapies. Skeletal muscle is central to diseases with high societal impact and those that do not have adequate animal models, including diabetes, obesity, and different dystrophies. The need for an accurate preclinical model of human skeletal muscle was exemplified by the market withdrawal of cerivastatin that was well tolerated in mice but caused fatal rhabdomyolysis in humans (von Keutz and Schluter, 1998; Thompson et al, 2006)
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