MyoScreen, a High-Throughput Phenotypic Screening Platform Enabling Muscle Drug Discovery

Area of Science:

• Biotechnology
• Drug Discovery
• Skeletal Muscle Physiology

Background:

• Current in vitro models for muscle atrophy lack physiological accuracy and high information content for drug discovery.
• Effective preclinical assays are needed to accelerate the development of novel therapies for muscle-wasting diseases.

Purpose of the Study:

• To develop and validate MyoScreen, a high-throughput, high-content screening platform for discovering and testing novel muscle therapeutics.
• To create a physiologically relevant in vitro model of human skeletal muscle for drug screening.

Main Methods:

• Integration of a micropatterned human primary skeletal muscle model with phenotypic and functional assays.
• Utilizing a fully automated platform for quantitative measurement of myogenesis, hypertrophy, atrophy, acetylcholine receptor (AChR) clusterization, intracellular calcium dynamics, and contractility.
• Performing a primary screen of 2560 compounds to identify myofiber regeneration and repair stimulators.

Main Results:

• MyoScreen myotubes exhibit aligned, striated myofibers with nerve-independent AChR accumulation and excitation-contraction coupling (ECC).
• The platform demonstrates reproducibility and sensitivity in various muscle assays, including contractility.
• A primary screen identified compounds that stimulate myofiber regeneration, with two hits further validated.

Conclusions:

• MyoScreen provides a robust and versatile platform for high-throughput, high-content screening of skeletal muscle therapeutics.
• This model enhances the predictive accuracy of preclinical drug selection, enabling earlier identification of efficacious chemical entities.
• MyoScreen represents a significant advancement over existing in vitro muscle models for drug discovery pipelines.