Thyroid hormones and skeletal muscle--new insights and potential implications

Abstract

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.

Figure 1

The role of thyroid hormone signalling in skeletal myogenesis. During muscle fibre development and in muscle regeneration, quiescent muscle satellite cells (MSC) that are characterized by the expression of the transcription factor PAX 7 require the induction of MYOD1 and MYF5 for their activation and entry into the cell cycle. T₃ promotes MSC differentiation by inducing MYOD1 expression. In addition, T₃ signalling is involved in the upregulation of the myogenic regulatory factor (MRF) family member Myogenin in immature myotubes and some isoforms of the myosin heavy chain (MyHC) in mature myotubes, thereby impacting muscle function.

Figure 2

The thyroid hormone signalling cascade in myotube differentiation. Thyroid hormone signalling is involved in the differentiation of quiescent muscle satellite cells (MSCs) into myotubes. Differentiating MSCs express the transcription factor FOXO3, which, in turn, induces expression of type 2 iodothyronine deiodinase (DIO2). DIO2 catalyzes the monodeiodination of the prohormone T₄ to produce the active hormone isoform T₃. T₃ then enters the nucleus, binds to the nuclear thyroid-hormone receptors, and activates transcription of MYOD1 and other downstream myogenic regulatory factors (MRFs) that lead to myotube differentiation.