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

Dennhag, Nils ; Kahsay, Abraha ; Nissen, Itzel ; Nord, Hanna ; Chermenina, Maria ; Liu, Jiao ; Arner, Anders LU ; Liu, Jing Xia ; Backman, Ludvig J. and Remeseiro, Silvia , et al. (2024) In Nature Communications 15(1).
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
15
issue
1
article number
1950
publisher
Nature Publishing Group
external identifiers
  • pmid:38431640
  • scopus:85186557555
ISSN
2041-1723
DOI
10.1038/s41467-024-46187-x
language
English
LU publication?
yes
id
1254be07-79a1-436e-8283-03e5d5235f46
date added to LUP
2024-03-14 09:58:55
date last changed
2024-04-25 06:34:32
@article{1254be07-79a1-436e-8283-03e5d5235f46,
  abstract     = {{<p>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.</p>}},
  author       = {{Dennhag, Nils and Kahsay, Abraha and Nissen, Itzel and Nord, Hanna and Chermenina, Maria and Liu, Jiao and Arner, Anders and Liu, Jing Xia and Backman, Ludvig J. and Remeseiro, Silvia and von Hofsten, Jonas and Pedrosa Domellöf, Fatima}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{fhl2b mediates extraocular muscle protection in zebrafish models of muscular dystrophies and its ectopic expression ameliorates affected body muscles}},
  url          = {{http://dx.doi.org/10.1038/s41467-024-46187-x}},
  doi          = {{10.1038/s41467-024-46187-x}},
  volume       = {{15}},
  year         = {{2024}},
}