Thyroid hormone has major effects on the development, regeneration and function of skeletal muscle. Thyroid hormone receptor ?1 is the predominant mediator of muscle T3 action, and transcriptionally regulates a number of important genes including SERCA A1 and A2, UCP 3 and GLUT 4, as well as the muscle differentiation factors myogenin and MyoD1. Circulating T3 enters myocytes via specific transporters such as MCT8 and 10, but we have shown in the last cycle of this grant that a significant fraction of cellular T3 is generated by the intracellular monodeiodination of T4 catalyzed by the type 2 iodothyronine deiodinase (D2). While mature myocytes are stable, skeletal muscle has a robust regenerative mechanism that is markedly accelerated following injury. This involves the concerted actions of satellite cells, the muscle stem cell equivalent, an a number of different cell types localized to the muscle stem cell niche including resident stromal fibro/adipogenic progenitors (FAPs), T-regulatory cells, and macrophages. These cells produce a number of pro-myogenic cytokines and growth factors that that are necessary to coordinate the regeneration process including Notch, Wnt/?-catenin, sonic hedgehog, IL-4 and IL-6, and a number of TGF-??family members among others. During the last grant period, we showed that changes in thyroid hormone mediated by local thyroid hormone metabolism play an important role in these signaling cascades. We found that after muscle injury acute inactivation of thyroid hormone by the type 3 iodothyronine deiodinase (D3) is necessary to facilitate satellite cell proliferation and block premature differentiation that otherwise would lead to apoptosis. This is followed by increased type 2 deiodinase (D2)-mediated T4 activation that is essential for the satellite cell to differentiate into mature myoblasts and then myofibers to complete the normal muscle regeneration program. In studies employing gene knockout mouse models, we have found that a loss of either D3 of D2 dramatically impedes muscle repair after injury. Using a murine model of satellite cell transplantation therapy, we further showed that local thyroid hormone activation by D2 plays a crucial role in the engraftment of transplanted muscle stem cells. In this renewal, we propose to combine studies using our unique mouse knockout models and established FACS-sorting isolation of specific cell types. We will investigate why D2 is required for engrafted satellite cell survival and successful myotube formation, how D3 and D2 change after injury in satellite cells and other components of the muscle stem cell niche, whether deiodinases are required for the coordinated responses of other cell types in the muscle stem cell niche, and how dysregulation of this process may lead to fibrosis. This will expand our knowledge of the contributions of thyroid hormone to muscle regeneration and form the basis for potential therapeutic strategies for patients with skeletal muscle injuries.

Public Health Relevance

We have found that thyroid hormone (T3) levels in skeletal muscle are very tightly regulated by intra-tissue activation and inactivation, and if this is lost injured muscle is unable to fully repair itself. We will define how T3 controls muscle repair in multiple cell types using biochemical and molecular biologic techniques with the goal of discovering therapies to enhance muscle regeneration after injury in: the elderly, athletes, individuals with accidental and occupational injuries, and patients with chronic degenerative muscle disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK044128-24
Application #
9271179
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Silva, Corinne M
Project Start
1992-01-15
Project End
2019-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
24
Fiscal Year
2017
Total Cost
$534,579
Indirect Cost
$214,579
Name
Brigham and Women's Hospital
Department
Type
Independent Hospitals
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Wassner, Ari J; Jugo, Rebecca H; Dorfman, David M et al. (2017) Myocardial Induction of Type 3 Deiodinase in Dilated Cardiomyopathy. Thyroid 27:732-737
Luongo, Cristina; Martin, Cecilia; Vella, Kristen et al. (2015) The selective loss of the type 2 iodothyronine deiodinase in mouse thyrotrophs increases basal TSH but blunts the thyrotropin response to hypothyroidism. Endocrinology 156:745-54
Wittmann, Gábor; Harney, John W; Singru, Praful S et al. (2014) Inflammation-inducible type 2 deiodinase expression in the leptomeninges, choroid plexus, and at brain blood vessels in male rodents. Endocrinology 155:2009-19
Salvatore, Domenico; Simonides, Warner S; Dentice, Monica et al. (2014) Thyroid hormones and skeletal muscle--new insights and potential implications. Nat Rev Endocrinol 10:206-14
Dentice, Monica; Ambrosio, Raffaele; Damiano, Valentina et al. (2014) Intracellular inactivation of thyroid hormone is a survival mechanism for muscle stem cell proliferation and lineage progression. Cell Metab 20:1038-48
Maynard, Michelle A; Marino-Enriquez, Adrian; Fletcher, Jonathan A et al. (2014) Thyroid hormone inactivation in gastrointestinal stromal tumors. N Engl J Med 370:1327-34
Zavacki, Ann Marie; Larsen, P Reed (2013) RTH?, a newly recognized phenotype of the resistance to thyroid hormone (RTH) syndrome in patients with THRA gene mutations. J Clin Endocrinol Metab 98:2684-6
Dentice, Monica; Marsili, Alessandro; Zavacki, Annmarie et al. (2013) The deiodinases and the control of intracellular thyroid hormone signaling during cellular differentiation. Biochim Biophys Acta 1830:3937-45
Hong, Eun-Gyoung; Kim, Brian W; Jung, Dae Young et al. (2013) Cardiac expression of human type 2 iodothyronine deiodinase increases glucose metabolism and protects against doxorubicin-induced cardiac dysfunction in male mice. Endocrinology 154:3937-46
Larsen, P Reed; Zavacki, Ann Marie (2012) The role of the iodothyronine deiodinases in the physiology and pathophysiology of thyroid hormone action. Eur Thyroid J 1:232-242

Showing the most recent 10 out of 54 publications