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.
View: Text | PDF
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

×

Figure 1

D2, expressed in mpc, is induced during differentiation and enhances intracellular thyroid hormone signaling.

Options: View larger image (or click on image) Download as PowerPoint
D2, expressed in mpc, is induced during differentiation and enhances int...
(A) Dio2 mRNA (top) and activity (bottom) in mouse TA muscles at indicated ages. Data are expressed as mean ± SEM of at least 3 independent experiments. *P < 0.05, **P < 0.01 compared with P1 mice; n = 6. (B) Mouse primary pp6 cells were isolated from newborn mouse skeletal muscle (see Methods) and cultured in proliferative (PROL) or differentiating (DIFF) conditions for 48 hours before measurement of Dio2 mRNA (top) and activity (bottom). (C) Differentiation was induced in C2C12 cells, and Dio2 and MyoD mRNA expression was measured by RT-PCR at the indicated times. (D) C2C12 cells (left) or C2C12 cells stably transfected with control (shCTR) or specific D2 shRNA plasmid (shD2) (right) were transiently cotransfected with a T3-responsive reporter (TRE3TK-Luc) and CMV-Renilla plasmid as internal standard, and differentiation was induced for the indicated times. The Luc/Renilla value from mock-transfected plasmid was arbitrarily set as 1. (E) C2C12 cells were transfected with the indicated plasmids and TRE3TK-Luc reporter and MyoD levels measured thereafter. Error bars represent SD.