Fast, multiplexable and efficient somatic gene deletions in adult mouse skeletal muscle fibers using AAV-CRISPR/Cas9

Marco Thürkauf, Shuo Lin, Filippo Oliveri, Dirk Grimm, Randall J. Platt and Markus A. Rüegg ()
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Marco Thürkauf: University of Basel
Shuo Lin: University of Basel
Filippo Oliveri: University of Basel
Dirk Grimm: Heidelberg University
Randall J. Platt: ETH Zurich
Markus A. Rüegg: University of Basel

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Molecular screens comparing different disease states to identify candidate genes rely on the availability of fast, reliable and multiplexable systems to interrogate genes of interest. CRISPR/Cas9-based reverse genetics is a promising method to eventually achieve this. However, such methods are sorely lacking for multi-nucleated muscle fibers, since highly efficient nuclei editing is a requisite to robustly inactive candidate genes. Here, we couple Cre-mediated skeletal muscle fiber-specific Cas9 expression with myotropic adeno-associated virus-mediated sgRNA delivery to establish a system for highly effective somatic gene deletions in mice. Using well-characterized genes, we show that local or systemic inactivation of these genes copy the phenotype of traditional gene-knockout mouse models. Thus, this proof-of-principle study establishes a method to unravel the function of individual genes or entire signaling pathways in adult skeletal muscle fibers without the cumbersome requirement of generating knockout mice.

Date: 2023
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DOI: 10.1038/s41467-023-41769-7

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