Abstract
BackgroundDiabetes 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 FindingsWe 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 obese 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 TRα1. This function is driven by the N-terminal part of the protein. Moreover, DOR physically interacts with TR α1 and to T3-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/SignificanceOur 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 the alterations in muscle function associated with this disease.
Highlights
Thyroid hormones play a central role in metabolic homeostasis, development, cell differentiation and growth [1,2,3]
To identify potential risk factors for the alterations associated with type 2 diabetes, we screened genes differentially expressed in Zucker diabetic fatty (ZDF) rats and non-diabetic lean rats by PCR-select cDNA subtraction
Given that DOR expression is markedly repressed in muscle from ZDF rats and that diabetes is linked to skeletal muscle atrophy [27,28,29,30], we studied whether DOR participates in myogenesis
Summary
Thyroid hormones play a central role in metabolic homeostasis, development, cell differentiation and growth [1,2,3]. The major effects of thyroid hormones are mediated by modulation of gene transcription. Diabetes is characterized by reduced thyroid function and altered myogenesis after muscle injury. We identify a novel component of thyroid hormone action that is repressed in diabetic rat muscle. 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. DOR enhances the transcriptional activity of the thyroid hormone receptor TRa1. This function is driven by the N-terminal part of the protein. DOR expression is down-regulated in skeletal muscle in diabetes This finding may be of relevance for the alterations in muscle function associated with this disease
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