Abstract
Severely damaged adult zebrafish extraocular muscles (EOMs) regenerate through dedifferentiation of residual myocytes involving a muscle-to-mesenchyme transition. Members of the Twist family of basic helix-loop-helix transcription factors (TFs) are key regulators of the epithelial-mesenchymal transition (EMT) and are also involved in craniofacial development in humans and animal models. During zebrafish embryogenesis, twist family members (twist1a, twist1b, twist2, and twist3) function to regulate craniofacial skeletal development. Because of their roles as master regulators of stem cell biology, we hypothesized that twist TFs regulate adult EOM repair and regeneration. In this study, utilizing an adult zebrafish EOM regeneration model, we demonstrate that inhibiting twist3 function using translation-blocking morpholino oligonucleotides (MOs) impairs muscle regeneration by reducing myocyte dedifferentiation and proliferation in the regenerating muscle. This supports our hypothesis that twist TFs are involved in the early steps of dedifferentiation and highlights the importance of twist3 during EOM regeneration.
Highlights
Skeletal muscle injuries and degenerative conditions are common, debilitating, and significant causes of morbidity and mortality worldwide [1, 2]
Utilizing our established regeneration model, we report that twist3 is the sole twist transcription factors (TFs) required for extraocular muscles (EOMs) regeneration in adult zebrafish
Because of their role as master regulators of stem cells and in embryonic craniofacial development, we decided to use our unique zebrafish EOM regeneration model to test whether twist TFs play a role in EOM myocyte dedifferentiation
Summary
Skeletal muscle injuries and degenerative conditions are common, debilitating, and significant causes of morbidity and mortality worldwide [1, 2]. Despite the pervasiveness of injury, mammalian muscle repair is limited by the extent of tissue damage and restricted by the amount of resident stem cells (i.e. satellite cells) available for tissue replacement [3]. This differs from non-mammalian vertebrates such as zebrafish which robustly regenerate both skeletal and cardiac muscle as well as other tissues including retina, spinal cord, liver, and fin [4,5,6,7,8].
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