Thyroid hormone (TH) is required for normal growth, development and function of nearly all human tissues. This proposal will examine how TH controls skeletal muscle differentiation, regeneration and function. Skeletal muscle is a well-recognized TH target. TH controls resting energy expenditure in large part through its effects on skeletal muscle metabolism. A dramatic example of the effect of TH on muscle regeneration occurs in the dystrophic (mdx) mouse in which experimental thyrotoxicosis accelerates myocyte destruction, while this process is retarded when mice are made hypothyroid. Despite this and the muscle dysfunction in hypothyroid and thyrotoxic patients, the mechanism(s) for the actions of TH in skeletal muscle are poorly understood. The first step in TH action is the 5'monodeiodination of the prohormone T4, to form 3,5,3'triiodothyronine (T3) by the types 1 and 2 selenodeiodinases (D1 and D2). The T3 formed accounts for most of the actions of T4. The effects of T3 require its binding to nuclear receptors (TR1 and TR2). Termination of the effects of T3 and prevention of T4 activation is catalyzed by removal of one or both inner ring iodines from the iodothyronine nucleus by the type 3 deiodinase (D3). Both the T4-activating D2 (but not D1) and the T4- and T3-inactivating D3 are expressed in the satellite cells which are the muscle stem cell equivalent. The presence of these deiodinases allows regulation of the intracellular satellite cell T3 concentration in response to various cellular cues independent of the circulating TH levels. A striking example occurs after experimental muscle injury which induces an increases in Notch, Wnt/2-catenin, Sonic hedgehog, Tgf2, and Hif11, among others, all of which are known to activate the Dio3 gene. This leads to a transient early increase of D3 in the injured region lasting 8-10 days and is associated with the expansion of the satellite and myoblast precursor cells. A FoxO3- mediated increase in D2 follows increasing intracellular T4 to T3 conversion. The increase in intracellular T3 facilitates differentiation of the myoblast precursor pool replacing the damaged myocytes. Circulating thyroid hormone concentrations remain constant throughout. In a Dio2 null (D2KO) mouse, which maintains a normal circulating T3 concentration, the repair of injured muscle is markedly delayed and the T3-dependent MyoD1 and its downstream targets remain low, indicating an increase in intracellular D2-mediated T3 production is required for normal regeneration and differentiation. This project will evaluate the effects of the dynamic changes in intracellular T3 in muscle produced by the actions of D3 and D2 using genetic and biochemical techniques. We will explore how these changes facilitate skeletal muscle differentiation and regeneration. We will also determine whether therapeutic manipulations of deiodinase activities could be used to enhance the treatment of conditions such as traumatic or degenerative muscle injury or the sarcopenia of the elderly.
Our studies will employ biochemical and molecular biological techniques to understand what steps in skeletal muscle development and regeneration require thyroid hormone. We will then determine whether deficits in these pathways are responsible for, or could be used to enhance therapy of muscle injury, the impaired muscle regeneration in the elderly, or that occurring in chronic degenerative muscle disease.
|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|
|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|
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|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|
|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|
|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|
|Marsili, Alessandro; Tang, Dan; Harney, John W et al. (2011) Type II iodothyronine deiodinase provides intracellular 3,5,3'-triiodothyronine to normal and regenerating mouse skeletal muscle. Am J Physiol Endocrinol Metab 301:E818-24|
|Ramadan, W; Marsili, A; Huang, S et al. (2011) Type-2 iodothyronine 5'deiodinase in skeletal muscle of C57BL/6 mice. I. Identity, subcellular localization, and characterization. Endocrinology 152:3082-92|
|Ramadan, W; Marsili, A; Larsen, P R et al. (2011) Type-2 iodothyronine 5'deiodinase (D2) in skeletal muscle of C57Bl/6 mice. II. Evidence for a role of D2 in the hypermetabolism of thyroid hormone receptor alpha-deficient mice. Endocrinology 152:3093-102|
|Hamnvik, Ole-Petter Riksfjord; Larsen, P Reed; Marqusee, Ellen (2011) Thyroid dysfunction from antineoplastic agents. J Natl Cancer Inst 103:1572-87|
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