Type 2 Iodothyronine Deiodinase in Skeletal Muscle: Effects of Hypothyroidism and Fasting

Abstract

Context:The iodothyronine deiodinases D1, D2, and D3 enable tissue-specific adaptation of thyroid hormone levels in response to various conditions, such as hypothyroidism or fasting. The possible expression of D2 mRNA in skeletal muscle is intriguing because this enzyme could play a role in systemic as well as local T 3 production.Objective: We determined D2 activity and D2 mRNA expression in human skeletal muscle biopsies under control conditions and during hypothyroidism, fasting, and hyperinsulinemia.Design: This was a prospective study. Setting:The study was conducted at a university hospital. Patients:We studied 11 thyroidectomized patients with differentiated thyroid carcinoma (DTC) on and after 4 wk off T 4 replacement and six healthy lean subjects in the fasting state and during hyperinsulinemia after both 14 and 62 h of fasting.Mean Outcome Measures: D2 activity and D2 mRNA levels were measured in skeletal muscle samples.Results: No differences were observed in muscle D2 mRNA levels in DTC patients on and off T 4 replacement therapy. In healthy subjects, muscle D2 mRNA levels were lower after 62 h compared to 14 h of fasting. Insulin increased mRNA expression after 62 h, but not after 14 h of fasting. Skeletal muscle D2 activities were very low and not influenced by hypothyroidism and fasting. Conclusion:Human skeletal muscle D2 mRNA expression is modulated by fasting and insulin, but not by hypothyroidism. The lack of a clear effect of D2 mRNA modulation on the observed low D2 activities questions the physiological relevance of D2 activity in human skeletal muscle. (J Clin Endocrinol Metab 94: 2144 -2150, 2009) P eripheral thyroid hormone metabolism is mainly regulated by the iodothyronine deiodinases D1, D2, and D3 (1, 2). D1 is expressed in liver, kidney, thyroid, and at a lower level in the pituitary. This enzyme converts the prohormone T 4 to active T 3 and is very active in the breakdown of rT 3 (1, 3). Although D1 contributes significantly to peripheral T 4 to T 3 conversion, it is probably not the major source of extrathyroidal T 3 production in humans (1, 2, 4, 5). D2 also catalyzes the production of T 3

Coupling between Nutrient Availability and Thyroid Hormone Activation

“…7). These data provide a mechanistic explanation for the observation in humans that fasting is associated with a reduction in skeletal muscle D2 activity that is partially prevented by insulin administration (43). The present findings constitute a new aspect of the overarching homeostatic role played by the hypothalamic-pituitary-thyroid axis to adjust thyroid hormone activation to the appropriate level of energy substrates; thyroidal activity and serum T 3 levels are kept at a minimum (default) during fasting or severe caloric restriction, and both increase as food becomes available.…”

Skeletal muscle deiodinase type 2 regulation during illness in mice

“…The decreased D2 expression after S. pneumoniae infection might also be due to diminished food-intake, as D2 expression decreases after fasting in healthy humans (Heemstra et al 2009). In addition, D2 mRNA expression also decreased in the pair-fed controls of the turpentine experiment.…”

The molecular basis of the non-thyroidal illness syndrome

“…Dio2 expression in skeletal muscle increases in intensive-care unit patients (Mebis et al 2007), in several NTIS animal models of acute (Kwakkel et al 2008) and chronic inflammation (Kwakkel et al 2009), while in septic patients and mice muscle Dio2 expression decreases (Rodriguez-Perez et al 2008, Kwakkel et al 2009). The increased Dio2 expression during chronic inflammation is likely due to enhanced CREB signalling (Kwakkel et al 2009), while the decrease during sepsis might be mediated by decreased food intake since 62 h of fasting decreased muscle Dio2 expression in healthy volunteers (Heemstra et al 2009) (see Fig. 3).…”