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.


RESULTS
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.


CONCLUSIONS
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.
Baumgartner
Bernhard G
BG
Institute for Research in Biomedicine (IRB Barcelona) and Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.
Orpinell
Meritxell
M
Duran
Jordi
J
Ribas
Vicent
V
Burghardt
Hans E
HE
Bach
Daniel
D
Villar
Ana Victoria
AV
Paz
José C
JC
González
Meritxell
M
Camps
Marta
M
Oriola
Josep
J
Rivera
Francisca
F
Palacín
Manuel
M
Zorzano
Antonio
A
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D006801:Humans; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D011988:Receptors, Thyroid Hormone / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013963:Thyroid Hormones / Q000502:physiology
D017931:DNA Primers; C530815:DOR protein, rat; D009124:Muscle Proteins; D011988:Receptors, Thyroid Hormone; D013963:Thyroid Hormones