title: Type II iodothyronine deiodinase provides intracellular 3,5,3'-triiodothyronine to normal and regenerating mouse skeletal muscle.
abstract: The FoxO3-dependent increase in type II deiodinase (D2), which converts the prohormone thyroxine (T(4)) to 3,5,3'-triiodothyronine (T(3)), is required for normal mouse skeletal muscle differentiation and regeneration. This implies a requirement for an increase in D2-generated intracellular T(3) under these conditions, which has not been directly demonstrated despite the presence of D2 activity in skeletal muscle. We directly show that D2-mediated T(4)-to-T(3) conversion increases during differentiation in C(2)C(12) myoblast and primary cultures of mouse neonatal skeletal muscle precursor cells, and that blockade of D2 eliminates this. In adult mice given (125)I-T(4) and (131)I-T(3), the intracellular (125)I-T(3)/(131)I-T(3) ratio is significantly higher than in serum in both the D2-expressing cerebral cortex and the skeletal muscle of wild-type, but not D2KO, mice. In D1-expressing liver and kidney, the (125)I-T(3)/(131)I-T(3) ratio does not differ from that in serum. Hypothyroidism increases D2 activity, and in agreement with this, the difference in (125)I-T(3)/(131)I-T(3) ratio is increased further in hypothyroid wild-type mice but not altered in the D2KO. Notably, in wild-type but not in D2KO mice, the muscle production of (125)I-T(3) is doubled after skeletal muscle injury. Thus, D2-mediated T(4)-to-T(3) conversion generates significant intracellular T(3) in normal mouse skeletal muscle, with the increased T(3) required for muscle regeneration being provided by increased D2 synthesis, not by T(3) from the circulation.
authors.affiliation: Thyroid Section, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Marsili
authors.forename: Dan
authors.initials: D
authors.lastname: Tang
authors.forename: John W
authors.initials: JW
authors.lastname: Harney
authors.forename: Prabhat
authors.initials: P
authors.lastname: Singh
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Zavacki
authors.forename: Monica
authors.initials: M
authors.lastname: Dentice
authors.forename: Domenico
authors.initials: D
authors.lastname: Salvatore
authors.forename: P Reed
authors.initials: PR
authors.lastname: Larsen
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000502:physiology*; D032446:Myoblasts / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D012038:Regeneration / Q000502:physiology; D014284:Triiodothyronine / Q000378:metabolism*; D014285:Triiodothyronine, Reverse / Q000494:pharmacology; D000097564:Iodothyronine Deiodinase Type II
chemical_list: D007453:Iodide Peroxidase; D007457:Iodine Radioisotopes; D014284:Triiodothyronine; D014285:Triiodothyronine, Reverse; D000097564:Iodothyronine Deiodinase Type II