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

• Published in: PloS one 2007-11, Vol.2 (11), p.e1183
• Main Authors: Baumgartner, Bernhard G, Orpinell, Meritxell, Duran, Jordi, Ribas, Vicent, Burghardt, Hans E, Bach, Daniel, Villar, Ana Victoria, Paz, José C, González, Meritxell, Camps, Marta, Oriola, Josep, Rivera, Francisca, Palacín, Manuel, Zorzano, Antonio
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animal tissues; Animals; Base Sequence; Cell cycle; Cloning; Cytokines; Diabetes; Diabetes and Endocrinology; Diabetes and Endocrinology/Thyroid; Diabetes and Endocrinology/Type 2 Diabetes; Diabetes mellitus; Diabetis; DNA Primers; Fines & penalties; Gene expression; Genes; Genetic aspects; Hormones; Hormones tiroides; Humans; Injury prevention; Insulin; Insulin-like growth factors; Kinases; Localization; Metabolism; Molecular Sequence Data; Muscle Proteins - physiology; Muscle, Skeletal - metabolism; Musculoskeletal system; Myocardium - metabolism; Myogenesis; Obesity; Phosphorylation; Promoters; Proteins; Rates (Animals de laboratori); Rats; Rats as laboratory animals; Rats, Zucker; Receptors, Thyroid Hormone - chemistry; Receptors, Thyroid Hormone - drug effects; Receptors, Thyroid Hormone - genetics; Receptors, Thyroid Hormone - physiology; Reverse Transcriptase Polymerase Chain Reaction; Rodents; Skeletal muscle; Thyroid; Thyroid gland; Thyroid hormones; Thyroid Hormones - physiology; Transcription; Triiodothyronine; Tumor necrosis factor-TNF; Type 2 diabetes; Weight control
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0001183

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. 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 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 TR(alpha1). This function is driven by the N-terminal part of the protein. Moreover, DOR physically interacts with TR( alpha1) and to T(3)-responsive promoters, as shown by ChIP assays. T(3) 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. 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 the alterations in muscle function associated with this disease.