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. IntroductionThe active thyroid hormone 3,5,3′ triiodothyronine (T3) derives either directly from thyroid secretion or by the monodeiodination of the prohormone thyroxine (T4) by one of two iodothyronine selenodeiodinases. Type 1 deiodinase is expressed in the liver, kidney, and thyroid but not skeletal muscle of vertebrates, and T3 produced from T4 by this enzyme is largely released into the plasma. On the other hand, type 2 deiodinase (D2) is specifically expressed in the central nervous system, pituitary, thyroid gland, brown adipose tissue, retina, and skeletal muscle. Much of the T3 derived from D2-mediated deiodination remains within the cell (1). Thus, this deiodinase provides a mechanism by which thyroid hormone (TH) can be activated in a tissue-specific chronologically programmed fashion, such as during development, or in circumstances where there is a requirement for rapid increase in active TH in a specific tissue. The effectiveness of this mechanism has been shown in the D2-dependent feedback regulation by T4 of the thyrotropin-releasing hormone and thyroid-stimulating hormone (TSH) secretion by the hypothalamus and pituitary (2). A programmed transient increase in D2 is required for the proper increase in T3 at a critical time in the embryonic mouse brain (3) to allow normal development of the cochlea (4, 5), and a sympathetic nervous system-induced increase in D2 provides the cellular T3

Coupling between Nutrient Availability and Thyroid Hormone Activation

“…6A). This observation, along with previous studies indicating that FOXO3 interacts with the Dio2 gene (15), suggested that FOXO1 may be the key molecule mediating the effects of nutrient status and insulin signaling on Dio2. This suspicion was strengthened by the observation that there was synchronized FIGURE 4.…”

“…A functional FOXO3 binding site is located in the 5Ј-UTR of the human DIO2, positively regulating DIO2 expression in developing skeletal muscle (15). Although proteins in the FOXO family can potentially bind to the same DNA cis-elements, the FOXO1 binding site identified in the present studies is within the DIO2 promoter, close to the transcription start site.…”

“…D2 expression is controlled by transcriptional (i.e. cAMP, FOXO3, and NF-B) (14,15), translational (i.e. ER stress) (16), and post-translational mechanisms, such as ubiquitination and proteasomal degradation (17).…”

Physiological role and regulation of iodothyronine deiodinases: A 2011 update

“…Blocking D2 activity inhibits the differentiation of myoblasts into mature myotubes, which are kept in active proliferation phase. In vivo experiments mirror this requirement for an increase in intracellular T3 since the expression of T3-dependent genes is reduced in the muscle of D2KO mice, which also have an inadequate MyoD response to injury and a marked delay in muscle regeneration (64). These observations are very exciting, considering that the capacity to modulate the thyroid status of muscle precursors could be a valuable tool in designing cell-based therapies for patients with muscle disease.…”

“…During this process, thyroid hormones orchestrate a programmed sequence of cell death and proliferation during which many organs are remodeled or replaced. In this situation, T3 deficiency seems to promote proliferation of undifferentiated cells, whereas a decrease in D3 and an increase in D2 activity lead to differentiation (64). These changes in deiodinases are controlled by various developmental transcription factors that have just begun to be identified.…”