fhl2b mediates extraocular muscle protection in zebrafish models of muscular dystrophies and its ectopic expression ameliorates affected body muscles

Nils Dennhag, Abraha Kahsay, Itzel Nissen, Hanna Nord, Maria Chermenina, Jiao Liu, Anders Arner, Jing-Xia Liu, Ludvig J. Backman, Silvia Remeseiro, Jonas Hofsten () and Fatima Pedrosa Domellöf ()
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Nils Dennhag: Umeå University
Abraha Kahsay: Umeå University
Itzel Nissen: Umeå University
Hanna Nord: Umeå University
Maria Chermenina: Umeå University
Jiao Liu: Lund University
Anders Arner: Lund University
Jing-Xia Liu: Umeå University
Ludvig J. Backman: Umeå University
Silvia Remeseiro: Umeå University
Jonas Hofsten: Umeå University
Fatima Pedrosa Domellöf: Umeå University

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract In muscular dystrophies, muscle fibers loose integrity and die, causing significant suffering and premature death. Strikingly, the extraocular muscles (EOMs) are spared, functioning well despite the disease progression. Although EOMs have been shown to differ from body musculature, the mechanisms underlying this inherent resistance to muscle dystrophies remain unknown. Here, we demonstrate important differences in gene expression as a response to muscle dystrophies between the EOMs and trunk muscles in zebrafish via transcriptomic profiling. We show that the LIM-protein Fhl2 is increased in response to the knockout of desmin, plectin and obscurin, cytoskeletal proteins whose knockout causes different muscle dystrophies, and contributes to disease protection of the EOMs. Moreover, we show that ectopic expression of fhl2b can partially rescue the muscle phenotype in the zebrafish Duchenne muscular dystrophy model sapje, significantly improving their survival. Therefore, Fhl2 is a protective agent and a candidate target gene for therapy of muscular dystrophies.

Date: 2024
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DOI: 10.1038/s41467-024-46187-x

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