Identification of a novel modulator of thyroid hormone receptor-mediated action

Background. Diabetes is characterized by reduced thyroid function and altered myogenesis after muscle injury. Here we identify a novel component of thyroid hormone action that is repressed in diabetic rat muscle. Methodology/Principal Findings. We have identified a gene, named DOR, abundantly expressed in insulin-sensitive tissues such as skeletal muscle and heart, whose expression is highly repressed in muscle from ohese diabetic rats. DOR expression is up-regulated during muscle differentiation and its loss-of-function has a negative impact on gene expression programmes linked to myogenesis or driven by thyroid hormones. In agreement with this, DOR enhances the transcriptional activity of the thyroid hormone receptor TR_α1. This function is driven by the N-terminal part of the protein. Moreover, DOR physically interacts with TR_α1 and to TR_α1-responsive promoters, as shown by ChIP assays. T₃ stimulation also promotes the mobilization of DOR from its localization in nuclear PML bodies, thereby indicating that its nuclear localization and cellular function may be related. Conclusions/Signifance. Our data indicate that DOR modulates thyroid hormone function and controls myogenesis. DOR expression is down-regulated in skeletal muscle in diabetes, This finding may be of relevance for thp alterations in muscle function associated with this disease.