The FoxO3/type 2 deiodinase pathway is required for normal mouse myogenesis and muscle regeneration
Monica Dentice, … , P. Reed Larsen, Domenico Salvatore
Monica Dentice, … , P. Reed Larsen, Domenico Salvatore
Published October 11, 2010
Citation Information: J Clin Invest. 2010;120(11):4021-4030. https://doi.org/10.1172/JCI43670.
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Research Article Muscle biology

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

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.

Authors

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

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Figure 6

D2 is induced in muscle regeneration.

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D2 is induced in muscle regeneration. (A) Dio2 mRNA was measured by RT-P...
(A) Dio2 mRNA was measured by RT-PCR during muscle differentiation in wild-type mice. Regeneration was induced by cardiotoxin injection (see Methods) into the TA muscle. **P < 0.01, ***P < 0.001 compared with Dio2 mRNA at 4 days after injection; n = 5. (B) D2 enzymatic activity was measured from total lysates of TA muscles from wild-type mice in which regeneration was induced as in A (n = 5). *P < 0.05, P < 0.01, compared with D2 activity at 2 days after injection; n = 5. (C) The average of plasma T3 levels in wild-type and D2-null mice during the regeneration experiment. Values are mean ± SEM.