The thyroid hormone activating enzyme, type 2 deiodinase, induces myogenic differentiation by regulating mitochondrial metabolism and reducing oxidative stress

Abstract

Thyroid hormone (TH) is a key metabolic regulator that acts by coordinating short- and long-term energy needs. Accordingly, significant metabolic changes are observed depending on thyroid status. Although it is established that hyperthyroidism augments basal energy consumption, thus resulting in an enhanced metabolic state, the net effects on cellular respiration and generation of reactive oxygen species (ROS) remain unclear. To elucidate the effects of augmented TH signal in muscle cells, we generated a doxycycline-inducible cell line in which the expression of the TH-activating enzyme, type 2 deiodinase (D2), is reversibly turned on by the “Tet-ON” system. Interestingly, increased intracellular TH caused a net shift from oxidative phosphorylation to glycolysis and a consequent increase in the extracellular acidification rate. As a result, mitochondrial ROS production, and both the basal and doxorubicin-induced production of cellular ROS were reduced. Importantly, the expression of a set of antioxidant genes was up-regulated, and, among them, the mitochondrial scavenger Sod2 was specifically induced at transcriptional level by D2-mediated TH activation. Finally, we observed that attenuation of oxidative stress and increased levels of SOD2 are key elements of the differentiating cascade triggered by TH and D2, thereby establishing that D2 is essential in coordinating metabolic reprogramming of myocytes during myogenic differentiation. In conclusion, our findings indicate that TH plays a key role in oxidative stress dynamics by regulating ROS generation. Our novel finding that TH and its intracellular metabolism act as mitochondrial detoxifying agents sheds new light on metabolic processes relevant to muscle physiology.

Thyroid hormone induces progression and invasiveness of squamous cell carcinomas by promoting a ZEB-1/E-cadherin switch

“…D2 has frequently been associated with cell differentiation in various cellular contexts 4,30 . Surprisingly, we recently found abundant D2 expression in BCC and SCC cells—a finding that implicated D2 in epithelial cancer 10 .…”

Succinate accumulation induces mitochondrial reactive oxygen species generation and promotes status epilepticus in the kainic acid rat model

“…Filtration was used to prepare a single cell suspension. As per previous reports [33], a 5 μM Mito-SOX working solution was then prepared. Next, 1.0 mL of the 5 μM Mito-SOX reagent was applied as a cell loading solution in which cells were incubated for 10 min at 37 °C without light exposure.…”

Effect of dietary threonine on growth performance and muscle growth, protein synthesis and antioxidant-related signalling pathways of hybrid catfishPelteobagrus vachelli♀ ×Leiocassis longirostris♂

“…Moreover, myogenic differentiation is a highly orchestrated sequential programme to generate mature skeletal muscle (25) . Studies in C2C12 cells show myogenic differentiation is regulated by reactive oxygen species (26)(27)(28) . Previous studies have demonstrated that dietary Thr deficiency increased reactive oxygen species, malondialdehyde (MDA) and protein carbonyl (PC) contents and decreased antioxidant-related enzyme activities via the regulation of the NFE2-related factor 2 (Nrf2) signalling pathway in the gills of juvenile grass carp Ctenopharyngodon idellus (29) .…”