Thyroid hormone (T₃) rapidly activates p38 and AMPK in skeletal muscle in vivo

Abstract

Thyroid hormone (T(3)) regulates the function of many tissues within the body. The effects of T(3) have largely been attributed to the modulation of thyroid hormone receptor-dependent gene transcription. However, nongenomic actions of T(3) via the initiation of signaling events are emerging in a number of cell types. This study investigated the ability of short-term T(3) treatment to phosphorylate and, therefore, activate signaling proteins in rat tissues in vivo. The kinases investigated included p38, AMP-activated protein kinase (AMPK), and extracellular signal-regulated kinase (ERK) 1/2. Following 2 h of T(3) treatment, p38 and AMPK phosphorylation was increased in both the slow-twitch soleus and the fast-twitch plantaris muscles. In contrast, ERK1/2 was not activated in either muscle type. Neither p38 nor AMPK was affected in heart. However, AMPK activation was decreased by T(3) in liver. ERK1/2 activation was decreased by T(3) in heart, but increased in liver. Possible downstream consequences of T(3)-induced kinase phosphorylation were investigated by measuring cAMP response element binding protein (CREB) and thyroid hormone receptor DNA binding, as well as peroxisome proliferator-activated receptor-alpha coactivator-1 mRNA levels. Protein DNA binding to the cAMP or thyroid hormone response elements was unaltered by T(3). However, peroxisome proliferator-activated receptor-alpha coactivator-1 mRNA expression was increased following 12 h of T(3) treatment in soleus. These data are the first to characterize the effects of T(3) treatment on kinase phosphorylation in vivo. We show that T(3) rapidly modifies kinase activity in a tissue-specific fashion. Moreover, the T(3)-induced phosphorylation of p38 and AMPK in both slow- and fast-twitch skeletal muscles suggests that these events may be important in mediating hormone-induced increases in mitochondrial biogenesis in skeletal muscle.

Triiodothyronine induces UCP-1 expression and mitochondrial biogenesis in human adipocytes

“…The effects of TH on thermogenesis are both direct and indirect. Several transcriptional factors have been suggested as intermediary factors for the indirect effects (18). For example, C/EBP-␣ is a transcriptional activator of the promoter sequences of UCP-1 (49) and ablating C/EBP-␣ causes defects in UCP-1 expression (44) in BAT of mice.…”

Role of thyroid hormone in skeletal muscle physiology

“…T 3 increases the pH in L6 myoblasts from rat SM culture via phospholipase C and intracellular calcium mobilization (Incerpi et al 1999, D'Arezzo et al 2004. T 3 modifies the kinase activity of p38 and AMPK, which are important in mitochondrial biogenesis in SM fibres (Irrcher et al 2008).…”

Endothermy in birds: underlying molecular mechanisms

“…Triiodothyronine (T3) regulates UCP-1 gene expression in BAT via a thyroid binding element (Rabelo et al, 1995). Furthermore, thyroid hormones can modulate aerobic metabolic capacity by regulating Endothermy in birds mitochondrial biogenesis (Nelson et al, 1995) and PGC1α gene expression (Irrcher et al, 2008). The transcriptional coactivator PGC1α is a prominent metabolic regulator in mammals (Finck and Kelly, 2006;Puigserver and Spiegelman, 2003) and it has recently been shown to play a role in metabolic regulation in birds (Walter and Seebacher, 2007).…”