Thyroid hormone signalling is required for skeletal muscle development, contractile function and muscle regeneration
As skeletal muscle comprises 30–40% of body mass, the altered basal metabolic rate in patients with thyroid hormone excess or deficiency is largely due to changes in skeletal muscle energy turnover
Functional studies indicate that the active thyroid hormone isoform T3 signals predominantly through the thyroid-hormone receptor α1 (THRA1) isoform in skeletal muscle
Expression of the type 2 iodothyronine deiodinase (DIO2), which converts the prohormone T4 to the active thyroid hormone isoform T3, is increased in developing or injured muscles
In the absence of DIO2, the muscle-specific thyroid hormone-dependent gene expression programme fails to be induced in the stem-cell-like satellite cells of skeletal muscle, resulting in impaired muscle regeneration
Current studies suggest that the dynamic control of thyroid hormone activity through the regulation of deiodinase expression can be harnessed to optimize myogenesis in patients with muscle diseases or injury
Thyroid hormone signalling regulates crucial biological functions, including energy expenditure, thermogenesis, development and growth. The skeletal muscle is a major target of thyroid hormone signalling. The type 2 and 3 iodothyronine deiodinases (DIO2 and DIO3, respectively) have been identified in skeletal muscle. DIO2 expression is tightly regulated and catalyses outer-ring monodeiodination of the secreted prohormone tetraiodothyronine (T4) to generate the active hormone tri-iodothyronine (T3). T3 can remain in the myocyte to signal through nuclear receptors or exit the cell to mix with the extracellular pool. By contrast, DIO3 inactivates T3 through removal of an inner-ring iodine. Regulation of the expression and activity of deiodinases constitutes a cell-autonomous, pre-receptor mechanism for controlling the intracellular concentration of T3. This local control of T3 activity is crucial during the various phases of myogenesis. Here, we review the roles of T3 in skeletal muscle development and homeostasis, with a focus on the emerging local deiodinase-mediated control of T3 signalling. Moreover, we discuss these novel findings in the context of both muscle homeostasis and pathology, and examine how skeletal muscle deiodinase activity might be therapeutically harnessed to improve satellite-cell-mediated muscle repair in patients with skeletal muscle disorders, muscle atrophy or injury.
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Work described in this Review was supported by Telethon grant GGP00185 to D. Salvatore and NIH grant DK044128 to P. R. Larsen and D. Salvatore.
The authors declare no competing financial interests.
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Salvatore, D., Simonides, W., Dentice, M. et al. Thyroid hormones and skeletal muscle—new insights and potential implications. Nat Rev Endocrinol 10, 206–214 (2014). https://doi.org/10.1038/nrendo.2013.238
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