Type 2 deiodinase in muscle during health and disease
One of the major routes for metabolism of thyroid hormones is by deiodination through the iodothyronine deiodinases, an enzyme family consisting of three members, types 1 (D1), 2 (D2) and type 3 (D3). The outer ring of thyroxin (T4) can be deiodinated by D2, leading to the formation of active hormone, triiodothyronine (T3). D2 is expressed predominantly in the brain and pituitary, but also in brown adipose tissue and muscle. Within the cell, D2 is localized in the endoplasmic reticulum and it is negatively regulated by thyroid hormone both pre- and post-transcriptionally.
Human skeletal muscle D2 was believed to be involved not only in local T3 production but also in systemic production of T3 in the basal condition. However, this concept was recently challenged as skeletal muscle D2 is expressed only at very low levels under euthyroid conditions in healthy persons. In addition, muscle D2 mRNA expression was reported to be modulated by fasting and by insulin suggesting that muscle D2 is involved in energy metabolism. Finally, recent studies have reported alterations in muscle D2 expression during inflammation. Both acute and chronic inflammation increase D2 mRNA expression in skeletal muscle while bacterial sepsis is associated with decreased D2 expression. Septic patients often develop muscle dysfunction which is probably due to decreased mitochondrial activity and content. This may point to a role for D2 in muscle dysfunction during sepsis as thyroid hormones are involved in mitochondrial function and biogenesis.
In summary, D2 expression varies in skeletal muscle according to the type of inflammation. The changes in deiodinase expression are likely to result in altered local T3 availability which may affect muscle function. Our future studies will focus on the question whether the observed changes in thyroid hormone metabolism in muscle during inflammation are clinically relevant in terms of muscle (dys)function.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.