{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:02:33Z","timestamp":1788912153560,"version":"build-2803163510"},"reference-count":59,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,10,25]],"date-time":"2021-10-25T00:00:00Z","timestamp":1635120000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Skeletal muscle atrophy is a condition associated with various physiological and pathophysiological conditions, such as denervation, cachexia, and fasting. It is characterized by an altered protein turnover in which the rate of protein degradation exceeds the rate of protein synthesis, leading to substantial muscle mass loss and weakness. Muscle protein breakdown reflects the activation of multiple proteolytic mechanisms, including lysosomal degradation, apoptosis, and ubiquitin\u2013proteasome. Thyroid hormone (TH) plays a key role in these conditions. Indeed, skeletal muscle is among the principal TH target tissue, where TH regulates proliferation, metabolism, differentiation, homeostasis, and growth. In physiological conditions, TH stimulates both protein synthesis and degradation, and an alteration in TH levels is often responsible for a specific myopathy. Intracellular TH concentrations are modulated in skeletal muscle by a family of enzymes named deiodinases; in particular, in muscle, deiodinases type 2 (D2) and type 3 (D3) are both present. D2 activates the prohormone T4 into the active form triiodothyronine (T3), whereas D3 inactivates both T4 and T3 by the removal of an inner ring iodine. Here we will review the present knowledge of TH action in skeletal muscle atrophy, in particular, on the molecular mechanisms presiding over the control of intracellular T3 concentration in wasting muscle conditions. Finally, we will discuss the possibility of exploiting the modulation of deiodinases as a possible therapeutic approach to treat muscle atrophy.<\/jats:p>","DOI":"10.3390\/metabo11110730","type":"journal-article","created":{"date-parts":[[2021,10,25]],"date-time":"2021-10-25T21:42:05Z","timestamp":1635198125000},"page":"730","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Thyroid Hormone Action in Muscle Atrophy"],"prefix":"10.3390","volume":"11","author":[{"given":"Maria Angela","family":"De Stefano","sequence":"first","affiliation":[{"name":"Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaele","family":"Ambrosio","sequence":"additional","affiliation":[{"name":"Istituti di Ricovero e Cura a Carattere Scientifico, SDN, 80143 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tommaso","family":"Porcelli","sequence":"additional","affiliation":[{"name":"Department of Public Health, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianfranco","family":"Orlandino","sequence":"additional","affiliation":[{"name":"Azienda Ospedaliera Universitaria Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4556-7620","authenticated-orcid":false,"given":"Domenico","family":"Salvatore","sequence":"additional","affiliation":[{"name":"Department of Public Health, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Luongo","sequence":"additional","affiliation":[{"name":"Department of Public Health, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1210\/edrv.23.1.0455","article-title":"Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases","volume":"23","author":"Bianco","year":"2002","journal-title":"Endocr. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1038\/nrendo.2013.238","article-title":"Thyroid hormones and skeletal muscle\u2014New insights and potential implications","volume":"10","author":"Salvatore","year":"2014","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"560","DOI":"10.3389\/fphys.2018.00560","article-title":"Thyroid hormones play role in sarcopenia and myopathies","volume":"9","author":"Bloise","year":"2018","journal-title":"Front. Physiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1136\/jnnp.68.6.750","article-title":"Neuromuscular findings in thyroid dysfunction: A prospective clinical and electrodiagnostic study","volume":"68","author":"Duyff","year":"2000","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1042\/cs0660063","article-title":"Effect of treatment on skeletal muscle dysfunction in hypothyroidism","volume":"66","author":"Khaleeli","year":"1984","journal-title":"Clin. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4294","DOI":"10.1111\/febs.12253","article-title":"Mechanisms regulating skeletal muscle growth and atrophy","volume":"280","author":"Schiaffino","year":"2013","journal-title":"FEBS J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1242\/dmm.010389","article-title":"Cellular and molecular mechanisms of muscle atrophy","volume":"6","author":"Bonaldo","year":"2013","journal-title":"Dis. Models Mech."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1038\/s41574-019-0218-2","article-title":"Deiodinases and their intricate role in thyroid hormone homeostasis","volume":"15","author":"Luongo","year":"2019","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1126\/science.199941","article-title":"Pituitary nuclear 3,5,3\u2032-triiodothyronine and thyrotropin secretion: An explanation for the effect of thyroxine","volume":"198","author":"Silva","year":"1977","journal-title":"Science"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1210\/me.2010-0095","article-title":"Minireview: Thyroid hormone transporters: The knowns and the unknowns","volume":"25","author":"Visser","year":"2011","journal-title":"Mol. Endocrinol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"40128","DOI":"10.1074\/jbc.M300909200","article-title":"Identification of monocarboxylate transporter 8 as a specific thyroid hormone transporter","volume":"278","author":"Friesema","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1056\/NEJM199409293311306","article-title":"The molecular basis of thyroid hormone action","volume":"331","author":"Brent","year":"1994","journal-title":"N. Engl. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4021","DOI":"10.1172\/JCI43670","article-title":"The FoxO3\/type 2 deiodinase pathway is required for normal mouse myogenesis and muscle regeneration","volume":"120","author":"Dentice","year":"2010","journal-title":"J. Clin. Investig."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1016\/j.cmet.2014.10.009","article-title":"Intracellular inactivation of thyroid hormone is a survival mechanism for muscle stem cell proliferation and lineage progression","volume":"20","author":"Dentice","year":"2014","journal-title":"Cell Metab."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.stemcr.2020.12.009","article-title":"Absence of both thyroid hormone transporters MCT8 and OATP1C1 impairs neural stem cell fate in the adult mouse subventricular zone","volume":"16","author":"Luongo","year":"2021","journal-title":"Stem Cell Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.1016\/j.molmet.2017.08.003","article-title":"Adult neural stem cell fate is determined by thyroid hormone activation of mitochondrial metabolism","volume":"6","author":"Gothie","year":"2017","journal-title":"Mol. Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"19689","DOI":"10.1038\/s41598-019-56156-w","article-title":"Gender-specific effects of transthyretin on neural stem cell fate in the subventricular zone of the adult mouse","volume":"9","author":"Vancamp","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1210\/en.2019-00088","article-title":"A global loss of Dio2 leads to unexpected changes in function and fiber types of slow skeletal muscle in male mice","volume":"160","author":"Carmody","year":"2019","journal-title":"Endocrinology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1172\/JCI26240","article-title":"Type 3 deiodinase is critical for the maturation and function of the thyroid axis","volume":"116","author":"Hernandez","year":"2006","journal-title":"J. Clin. Investig."},{"key":"ref_20","first-page":"R1545","article-title":"Effects of thyroid hormone receptor gene disruption on myosin isoform expression in mouse skeletal muscles","volume":"278","author":"Yu","year":"2000","journal-title":"Am. J. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1959","DOI":"10.1016\/j.stemcr.2018.03.021","article-title":"Thyroid hormone transporters MCT8 and OATP1C1 control skeletal muscle regeneration","volume":"10","author":"Mayerl","year":"2018","journal-title":"Stem Cell Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1089\/thy.2007.0256","article-title":"Thyroid hormone as a determinant of metabolic and contractile phenotype of skeletal muscle","volume":"18","author":"Simonides","year":"2008","journal-title":"Thyroid"},{"key":"ref_23","first-page":"81","article-title":"A methodological study in measuring T3 and T4 concentration in red and white skeletal muscle and plasma of euthyroid rats","volume":"90","author":"Janssen","year":"1979","journal-title":"Acta Endocrinol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5952","DOI":"10.1210\/en.2010-0631","article-title":"Type 2 iodothyronine deiodinase levels are higher in slow-twitch than fast-twitch mouse skeletal muscle and are increased in hypothyroidism","volume":"151","author":"Marsili","year":"2010","journal-title":"Endocrinology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.mce.2008.01.017","article-title":"T3-mediated expression of PGC-1alpha via a far upstream located thyroid hormone response element","volume":"287","author":"Wulf","year":"2008","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"101228","DOI":"10.1016\/j.redox.2019.101228","article-title":"The thyroid hormone activating enzyme, type 2 deiodinase, induces myogenic differentiation by regulating mitochondrial metabolism and reducing oxidative stress","volume":"24","author":"Sagliocchi","year":"2019","journal-title":"Redox Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1007\/978-981-13-1435-3_29","article-title":"Muscle atrophy: Present and Future","volume":"1088","author":"Cao","year":"2018","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1210\/en.2015-1632","article-title":"Thyroid hormone stimulation of autophagy is essential for mitochondrial biogenesis and activity in skeletal muscle","volume":"157","author":"Lesmana","year":"2016","journal-title":"Endocrinology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1210\/jcem-69-5-1082","article-title":"Effect of thyroid dysfunction on thigh muscle efficiency","volume":"69","author":"Zurcher","year":"1989","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1007\/s40520-018-1057-z","article-title":"Association of thyroid function with sarcopenia in elderly Chinese euthyroid subjects","volume":"31","author":"Sheng","year":"2019","journal-title":"Aging Clin. Exp. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"335","DOI":"10.2147\/CIA.S125934","article-title":"Low FT3: A possible marker of frailty in the elderly","volume":"12","author":"Bertoli","year":"2017","journal-title":"Clin. Interv. Aging"},{"key":"ref_32","first-page":"1399","article-title":"Endocrin myopathies and toxic myopathies","volume":"Volume 2","author":"Brown","year":"2002","journal-title":"Neuromuscular Function and Disease. Basic, Clinical and Electrodiagnostic Aspects"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"912","DOI":"10.3389\/fendo.2019.00912","article-title":"Thyroid hormone hyposensitivity: From genotype to phenotype and back","volume":"10","author":"Rurale","year":"2019","journal-title":"Front. Endocrinol."},{"key":"ref_34","first-page":"210","article-title":"Molecular and cell biology of skeletal muscle regeneration","volume":"3","author":"Grounds","year":"1993","journal-title":"Mol. Cell Biol. Hum. Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1152\/jappl.2001.91.2.534","article-title":"Myogenic satellite cells: Physiology to molecular biology","volume":"91","author":"Hawke","year":"2001","journal-title":"J. Appl. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1677\/joe.0.1710193","article-title":"Thyroid function and aging: Gender-related differences","volume":"171","author":"Moreira","year":"2001","journal-title":"J. Endocrinol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"C93","DOI":"10.1152\/ajpcell.1991.261.1.C93","article-title":"MHC composition and enzyme-histochemical and physiological properties of a novel fast-twitch motor unit type","volume":"261","author":"Larsson","year":"1991","journal-title":"Am. J. Physiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1111\/j.1748-1716.1993.tb09493.x","article-title":"An age-related type IIB to IIX myosin heavy chain switching in rat skeletal muscle","volume":"147","author":"Larsson","year":"1993","journal-title":"Acta Physiol. Scand."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1152\/physrev.00031.2010","article-title":"Fiber types in mammalian skeletal muscles","volume":"91","author":"Schiaffino","year":"2011","journal-title":"Physiol. Rev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"R57","DOI":"10.1530\/JOE-16-0611","article-title":"Role of thyroid hormone in skeletal muscle physiology","volume":"236","author":"Bloise","year":"2018","journal-title":"J. Endocrinol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1111\/j.1748-1716.1995.tb09841.x","article-title":"Thyroid hormone regulation of myosin heavy chain isoform composition in young and old rats, with special reference to IIX myosin","volume":"153","author":"Larsson","year":"1995","journal-title":"Acta Physiol. Scand."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5618","DOI":"10.1073\/pnas.0501559102","article-title":"Decline in skeletal muscle mitochondrial function with aging in humans","volume":"102","author":"Short","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1152\/physiol.00039.2014","article-title":"Mitochondria, muscle health, and exercise with advancing age","volume":"30","author":"Carter","year":"2015","journal-title":"Physiology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1152\/japplphysiol.01077.2015","article-title":"Effects of aging on mitochondrial function in skeletal muscle of American American Quarter Horses","volume":"121","author":"Li","year":"2016","journal-title":"J. Appl. Physiol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Casas, F., Pessemesse, L., Grandemange, S., Seyer, P., Baris, O., Gueguen, N., Ramonatxo, C., Perrin, F., Fouret, G., and Lepourry, L. (2009). Overexpression of the mitochondrial T3 receptor induces skeletal muscle atrophy during aging. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0005631"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/nrd1085","article-title":"Pharmacological strategies for muscular dystrophy","volume":"2","author":"Khurana","year":"2003","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1139\/o95-022","article-title":"Hypothyroidism prolongs and increases mdx muscle precursor proliferation and delays myotube formation in normal and dystrophic limb muscle","volume":"73","author":"McIntosh","year":"1995","journal-title":"Biochem. Cell Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1016\/0024-3205(91)90038-D","article-title":"Thyroidal involvement in the expression of avian muscular dystrophy","volume":"48","author":"King","year":"1991","journal-title":"Life Sci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1139\/o96-034","article-title":"Hyperthyroidism impairs early repair in normal but not dystrophic mdx mouse tibialis anterior muscle. An in vivo study","volume":"74","author":"Pernitsky","year":"1996","journal-title":"Biochem. Cell Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1002\/mus.880170413","article-title":"The effects of altered metabolism (hypothyroidism) on muscle repair in the mdx dystrophic mouse","volume":"17","author":"McIntosh","year":"1994","journal-title":"Muscle Nerve"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1172\/JCI119513","article-title":"Inhibitors of the proteasome reduce the accelerated proteolysis in atrophying rat skeletal muscles","volume":"100","author":"Tawa","year":"1997","journal-title":"J. Clin. Investig."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1002\/jcb.22329","article-title":"Experimental hyperthyroidism in rats increases the expression of the ubiquitin ligases atrogin-1 and MuRF1 and stimulates multiple proteolytic pathways in skeletal muscle","volume":"108","author":"Alamdari","year":"2009","journal-title":"J. Cell. Biochem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"799","DOI":"10.3177\/jnsv.44.799","article-title":"Effects of thyroid hormones on myofibrillar proteolysis and activities of calpain, proteasome, and cathepsin in primary cultured chick muscle cells","volume":"44","author":"Nakashima","year":"1998","journal-title":"J. Nutr. Sci. Vitaminol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2451","DOI":"10.1271\/bbb.67.2451","article-title":"Triiodothyronine but not thyroxine accelerates myofibrillar proteolysis via ATP production in cultured muscle cells","volume":"67","author":"Doi","year":"2003","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1073\/pnas.75.3.1369","article-title":"Thyroid hormones control lysosomal enzyme activities in liver and skeletal muscle","volume":"75","author":"DeMartino","year":"1978","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/s12929-019-0517-x","article-title":"Molecular functions and clinical impact of thyroid hormone-triggered autophagy in liver-related diseases","volume":"26","author":"Chi","year":"2019","journal-title":"J. Biomed. Sci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1016\/j.febslet.2010.01.056","article-title":"Autophagy in skeletal muscle","volume":"584","author":"Sandri","year":"2010","journal-title":"FEBS Lett."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/S0092-8674(04)00400-3","article-title":"Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy","volume":"117","author":"Sandri","year":"2004","journal-title":"Cell"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1007\/s10522-013-9432-9","article-title":"Signalling pathways regulating muscle mass in ageing skeletal muscle: The role of the IGF1-Akt-mTOR-FoxO pathway","volume":"14","author":"Sandri","year":"2013","journal-title":"Biogerontology"}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/11\/11\/730\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:23:15Z","timestamp":1760167395000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/11\/11\/730"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,25]]},"references-count":59,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["metabo11110730"],"URL":"https:\/\/doi.org\/10.3390\/metabo11110730","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,25]]}}}