title: Intracellular inactivation of thyroid hormone is a survival mechanism for muscle stem cell proliferation and lineage progression.
abstract: Precise control of the thyroid hormone (T3)-dependent transcriptional program is required by multiple cell systems, including muscle stem cells. Deciphering how this is achieved and how the T3 signal is controlled in stem cell niches is essentially unknown. We report that in response to proliferative stimuli such as acute skeletal muscle injury, type 3 deiodinase (D3), the thyroid hormone-inactivating enzyme, is induced in satellite cells where it reduces intracellular thyroid signaling. Satellite cell-specific genetic ablation of dio3 severely impairs skeletal muscle regeneration. This impairment is due to massive satellite cell apoptosis caused by exposure of activated satellite cells to the circulating TH. The execution of this proapoptotic program requires an intact FoxO3/MyoD axis, both genes positively regulated by intracellular TH. Thus, D3 is dynamically exploited in vivo to chronically attenuate TH signaling under basal conditions while also being available to acutely increase gene programs required for satellite cell lineage progression.
authors.affiliation: Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples 80131, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Dentice
authors.affiliation: IRCCS SDN, Naples 80143, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Ambrosio
authors.affiliation: Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples 80131, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Damiano
authors.affiliation: Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples 80131, Italy.
authors.forename: Annarita
authors.initials: A
authors.lastname: Sibilio
authors.affiliation: Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples 80131, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Luongo
authors.affiliation: Stem Cell Fate Laboratory, Institute of Genetics and Biophysics "A. Buzzati-Traverso," CNR, Naples 80131, Italy.
authors.forename: Ombretta
authors.initials: O
authors.lastname: Guardiola
authors.affiliation: Stem Cells & Development, Pasteur Institute, Paris 75015, France.
authors.forename: Siham
authors.initials: S
authors.lastname: Yennek
authors.affiliation: Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milano 20132, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Zordan
authors.affiliation: Stem Cell Fate Laboratory, Institute of Genetics and Biophysics "A. Buzzati-Traverso," CNR, Naples 80131, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Minchiotti
authors.affiliation: Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples 80131, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Colao
authors.affiliation: Thyroid Section, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Marsili
authors.affiliation: Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milano 20132, Italy; Dipartimento Scienze della Salute, Milano-Bicocca University, Milano 20126, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Brunelli
authors.affiliation: CEINGE-Biotecnologie Avanzate Scarl, Naples 80131, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Del Vecchio
authors.affiliation: Thyroid Section, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: P Reed
authors.initials: PR
authors.lastname: Larsen
authors.affiliation: Stem Cells & Development, Pasteur Institute, Paris 75015, France.
authors.forename: Shahragim
authors.initials: S
authors.lastname: Tajbakhsh
authors.affiliation: Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples 80131, Italy; CEINGE-Biotecnologie Avanzate Scarl, Naples 80131, Italy. Electronic address: domsalva@unina.it.
authors.forename: Domenico
authors.initials: D
authors.lastname: Salvatore
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000166:cytology*; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013234:Stem Cells / Q000166:cytology*; D013963:Thyroid Hormones / Q000378:metabolism*
chemical_list: D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D013963:Thyroid Hormones