Differential effects of thyroid hormones on energy metabolism of rat slow‐ and fast‐twitch muscles

Abstract

Thyroid hormone (TH) is an important regulator of mitochondrial content and activity. As mitochondrial content and properties differ depending on muscle-type, we compared mitochondrial regulation and biogenesis by T3 in slow-twitch oxidative (soleus) and fast-twitch mixed muscle (plantaris). Male Wistar rats were treated for 21 to 27 days with T3 (200 microg/kg/day). Oxidative capacity, regulation of mitochondrial respiration by substrates and phosphate acceptors, and transcription factors were studied. In soleus, T3 treatment increased maximal oxygen consumption (Vmax) and the activities of citrate synthase (CS) and cytochrome oxidase (COX) by 100%, 45%, and 71%, respectively (P < 0.001), whereas in plantaris only Vmax increased, by 39% (P < 0.01). ADP-independent respiration rate was increased in soleus muscle by 216% suggesting mitochondrial uncoupling. Mitochondrial substrate utilization in soleus was also influenced by T3, as were mitochondrial enzymes. Lactate dehydrogenase (LDH) activity was elevated in soleus and plantaris by 63% and 11%, respectively (P < 0.01), and soleus creatine kinase was increased by 48% (P < 0.001). T3 increased the mRNA content of the transcriptional co-activator of mitochondrial genes, PGC-1alpha, and the I and IV COX subunits in soleus. The muscle specific response to thyroid hormones could be explained by a lower content of TH receptors in plantaris than soleus. Moreover, TRalpha mRNA level decreased further after T3 treatment. These results demonstrate that TH has a major effect on mitochondrial content, regulation and coupling in slow oxidative muscle, but to a lesser extent in fast muscle, due to the high expression of TH receptors and PGC-1alpha transcription factor.

Role of thyroid hormone in skeletal muscle physiology

“…T 3 treatment increases maximal oxygen consumption, which is more than two times bigger in the soleus than in the plantaris, which are slow-twitch oxidative fibres and fast-twitch mixed SM, respectively (Bahi et al 2005). The stimulus for switching from a glycolytic fibre to an oxidative one increases not only mitochondrial content but also mitochondrial fusion, forming elongated mitochondria.…”

“…Overall, independent of the metabolized substrate, TH induces increased mitochondrial activity, oxidative phosphorylation and oxygen consumption through the stimulation of mitochondrial enzymes and UCP3 (Fig. 1B) (de Lange et al 2001, Bahi et al 2005.…”

“…The SM mitochondria of UCP3-deficient mice are more coupled and produce more reactive oxygen species (ROS) (Gong et al 2000, Vidal-Puig et al 2000, whereas the opposite effect was observed in mice overexpressing human UCP3 (Clapham et al 2000). T 3 also increases the expression of citrate synthase, which performs the first step of the citric acid cycle (Bahi et al 2005) and stimulates glycerol-3-phosphate dehydrogenase, a key enzyme of intermediary metabolism (Dümmler et al 1996). Furthermore, TH also stimulates oxidative phosphorylation in male rats due to the increased activity of cytochrome c oxidase 1 and 4 (COX1 and COX4, respectively), the last enzymes in the electron transport chain of mitochondria (Bahi et al 2005).…”

“…T 3 also increases the expression of citrate synthase, which performs the first step of the citric acid cycle (Bahi et al 2005) and stimulates glycerol-3-phosphate dehydrogenase, a key enzyme of intermediary metabolism (Dümmler et al 1996). Furthermore, TH also stimulates oxidative phosphorylation in male rats due to the increased activity of cytochrome c oxidase 1 and 4 (COX1 and COX4, respectively), the last enzymes in the electron transport chain of mitochondria (Bahi et al 2005). Additionally, healthy young men treated with T 3 for 14 days demonstrated an increase in RMR, UCP3 and UCP2 and a decrease in respiratory quotient, but did not show an increase COX4 or in nuclear respiratory factor 1 (NRF1) mRNA expression (Barbe et al 2001).…”

“…However, it is unknown whether there is a relationship between the substrate used and the TH levels. Therefore, the mechanism associated with T 3 increased SM mitochondrial activity, and oxygen consumption is related to the stimulation of mitochondrial enzymes and UCP3 (Barbe et al 2001, de Lange et al 2001, Bahi et al 2005.…”