The FoxO3/type 2 deiodinase pathway is required for normal mouse myogenesis and muscle regeneration

Monica Dentice, Alessandro Marsili, Raffaele Ambrosio, Ombretta Guardiola, Annarita Sibilio, Ji Hye Paik, Gabriella Minchiotti, Ronald A. DePinho, Gianfranco Fenzi, P. Reed Larsen, Domenico Salvatore

Research output: Contribution to journalArticle

Abstract

The active thyroid hormone 3,5,3′ triiodothyronine (T3) is a major regulator of skeletal muscle function. The deiodinase family of enzymes controls the tissue-specific activation and inactivation of the prohormone thyroxine (T4). Here we show that type 2 deiodinase (D2) is essential for normal mouse myogenesis and muscle regeneration. Indeed, D2-mediated increases in T3 were essential for the enhanced transcription of myogenic differentiation 1 (MyoD) and for execution of the myogenic program. Conversely, the expression of T3-dependent genes was reduced and after injury regeneration markedly delayed in muscles of mice null for the gene encoding D2 (Dio2), despite normal circulating T3 concentrations. Forkhead box O3 (FoxO3) was identified as a key molecule inducing D2 expression and thereby increasing intracellular T3 production. Accordingly, FoxO3-depleted primary myoblasts also had a differentiation deficit that could be rescued by high levels of T3. In conclusion, the FoxO3/D2 pathway selectively enhances intracellular active thyroid hormone concentrations in muscle, providing a striking example of how a circulating hormone can be tissue-specifically activated to influence development locally.

Original languageEnglish
Pages (from-to)4021-4030
Number of pages10
JournalJournal of Clinical Investigation
Volume120
Issue number11
DOIs
Publication statusPublished - Nov 1 2010

ASJC Scopus subject areas

  • Medicine(all)

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    Dentice, M., Marsili, A., Ambrosio, R., Guardiola, O., Sibilio, A., Paik, J. H., Minchiotti, G., DePinho, R. A., Fenzi, G., Larsen, P. R., & Salvatore, D. (2010). The FoxO3/type 2 deiodinase pathway is required for normal mouse myogenesis and muscle regeneration. Journal of Clinical Investigation, 120(11), 4021-4030. https://doi.org/10.1172/JCI43670