Resistance to thyroid hormone is associated with raised energy expenditure, muscle mitochondrial uncoupling, and hyperphagia

Abstract

Resistance to thyroid hormone (RTH), a dominantly inherited disorder usually associated with mutations in thyroid hormone receptor β (THRB), is characterized by elevated levels of circulating thyroid hormones (including thyroxine), failure of feedback suppression of thyrotropin, and variable tissue refractoriness to thyroid hormone action. Raised energy expenditure and hyperphagia are recognized features of hyperthyroidism, but the effects of comparable hyperthyroxinemia in RTH patients are unknown. Here, we show that resting energy expenditure (REE) was substantially increased in adults and children with THRB mutations. Energy intake in RTH subjects was increased by 40%, with marked hyperphagia particularly evident in children. Rates of muscle TCA cycle flux were increased by 75% in adults with RTH, whereas rates of ATP synthesis were unchanged, as determined by 13 C/ 31 P magnetic resonance spectroscopy. Mitochondrial coupling index between ATP synthesis and mitochondrial rates of oxidation (as estimated by the ratio of ATP synthesis to TCA cycle flux) was significantly decreased in RTH patients. These data demonstrate that basal mitochondrial substrate oxidation is increased and energy production in the form of ATP synthesis is decreased in the muscle of RTH patients and that resting oxidative phosphorylation is uncoupled in this disorder. Furthermore, these observations suggest that mitochondrial uncoupling in skeletal muscle is a major contributor to increased REE in patients with RTH, due to tissue selective retention of thyroid hormone receptor α sensitivity to elevated thyroid hormone levels.

A rare syndrome: Thyroid hormone resistance

“…Therefore mutations in the TRβ gene in RTH are associated with pituitary and liver resistance, as exemplified by normal serum sex-hormone-binding globulin and non-suppressed TSH levels seen in patients, while the tachycardia seen in many RTH cases may represent retention of cardiac sensitivity to elevated thyroid hormones acting via a normal TRα. 15 Interestingly, although positive correlations between free T3 and heart rate have been shown in RTH, heart rate was clearly normal range in spite of high free T3 levels in our index case. Moreover, normal presystolic ejection time was demonstrated during echocardiographic evaluation.…”

Role of thyroid hormone in skeletal muscle physiology

“…When the authors measured muscle substrate oxidation, they found an increased rate (75%) of tricarboxylic acid (TCA) cycle flux and decreased rates of ATP synthase flux, thus decreasing muscle mitochondrial energy uncoupling (ratio of TCA/ATP). Furthermore, the intramyocellular lipid content increased in the soleus muscle of RTH subjects compared to the control (Mitchell et al 2010).…”

“…Analysis of patient samples presenting with the classical form of resistance to TH (RTH-THRB mutation) demonstrated an increase in RMR compared to healthy individuals (Mitchell et al 2010). This increased RMR was due to the action of THRA in the muscle, which was responding to the TH excess seen in those patients.…”

The Δ337T mutation on the TRβ causes alterations in growth, adiposity, and hepatic glucose homeostasis in mice

“…05). This fact opposes what was seen in one study of patients with RTH where HOMA-IR was 50% elevated in patients carrying different mutations in heterozygosis (Mitchell et al 2010). We proceeded with the investigation on insulin sensitivity performing the glucose tolerance test and insulin sensitivity test on 12 h fasted mice (Fig.…”