Sagliocchi, Serena (2021) The thyroid hormone activating enzyme, type 2 deiodinase, induces myogenic differentiation by regulating mitochondrial metabolism and reducing oxidative stress. [Tesi di dottorato]

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Item Type:	Tesi di dottorato
Resource language:	English
Title:	The thyroid hormone activating enzyme, type 2 deiodinase, induces myogenic differentiation by regulating mitochondrial metabolism and reducing oxidative stress.
Creators:	Creators Email Sagliocchi, Serena ssagliocchi@gmail.com
Date:	December 2021
Number of Pages:	47
Institution:	Università degli Studi di Napoli Federico II
Department:	Sanità Pubblica
Dottorato:	Sanità pubblica e medicina preventiva
Ciclo di dottorato:	34
Coordinatore del Corso di dottorato:	nome email Troncone, Giancarlo giancarlo.troncone@unina.it
Tutor:	nome email Dentice, Monica UNSPECIFIED
Date:	December 2021
Number of Pages:	47
Keywords:	Thyroid Hormone, Oxidative stress, myogenic differenttiation.
Settori scientifico-disciplinari del MIUR:	Area 05 - Scienze biologiche > BIO/09 - Fisiologia
Date Deposited:	20 Dec 2021 13:47
Last Modified:	28 Feb 2024 11:34
URI:	http://www.fedoa.unina.it/id/eprint/14340

Collection description

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. Reactive oxygen species (ROS) are bioproducts of various ubiquitous cellular processes, and were long considered deleterious moieties that generate oxidative stress, disease and aging 1. However, it is now recognized that ROS is a molecular signal that regulates physiological cellular processes 2. Skeletal muscle is one of the most active ROS generating tissues, which is in line with its intense metabolic action. In physiologic conditions, mitochondrial ROS production is enhanced during muscle contraction, and superoxide generation can increase up to ∼100-fold during aerobic contractions 3. However, excess ROS levels promote mitochondria fragmentation and dysfunction, thereby altering the physiological turnover of muscle fibers 3,4. During muscle repair, ROS are physiologically active signaling molecules that trigger the cascade of events that enable correct muscle repair and activation of muscle stem cells (“satellite cells”) 5. However, prolonged exposure to elevated ROS levels can exacerbate muscle injury by inducing oxidative toxic damage to regenerating myofibers 5. Indeed, as in many other tissues, excess of ROS in skeletal muscle exacerbates muscular dystrophy 1, and other muscle diseases 4-7. The relative prevalence of the aforementioned “positive” or “negative” effects of ROS depends on complex intracellular mechanisms that maintain the ROS threshold within physiological concentrations. Thyroid hormone has a major impact on whole-body energy metabolism and on tissue-specific energy balance 8. Thyroid hormone modulates all metabolic signaling pathways and consequently, altered TH concentrations in humans are associated with profound changes in energy status 8. The extent of intramuscular TH action is determined both by the systemic levels of TH and by local regulation that modulates the nuclear availability of the hormone 9. Indeed, although the hypothalamic-pituitary-thyroid axis efficiently regulates TH homeostasis, thus maintaining circulating TH levels in a constant steady-state, its intracellular concentration can rapidly be attenuated or increased in- dependent of serum TH blood levels by the enzymatic control of the selenodeiodinases (D1, D2 and D3) that catalyze TH activation and catabolism 10. The actions of the three deiodinases, together with the uptake of T3 and T4 into the cell by specific transporters, constitute a mechanism of pre-receptor control of TH action at cellular level regardless of the constant serum T3 levels 10. The metabolic relevance of the deiodinases is exemplified by the effects of D2 on thermo-regulation and the consequent energy expenditure in brown adipose tissue (BAT) 11,12. Cold exposure causes an increase in the sympathetic activity of BAT, which, in turn, increases lipolysis, mitochondrial uncoupling and D2 activity 13. In the absence of D2-generated T3, there is a decrease in Ucp-1 gene expression and impaired adaptive thermogenesis 11. In skeletal muscle, D2 expression is barely detectable under basal conditions, however its expression is markedly increased during muscle regeneration 14. We previously demonstrated that D2 is functionally relevant in muscle stem cells and that loss of D2 severely impairs muscle repair after injury 14,15. These findings raise the intriguing possibility that, similar to BAT, D2 is a “master regulator” of overall energy metabolism in skeletal muscle during the regeneration process. To determine the metabolic relevance of intracellular D2-mediated TH changes in muscle cells, we generated a muscle cell line (pTRE-D2) in which D2 can be reversibly induced by doxycycline. We found that induction of D2 induces a shift toward glycolytic metabolism. Importantly, D2 induction decreased basal levels of ROS and induced a parallel up-regulation of the detoxifying gene Sod2. The D2-mediated TH activation led to detoxifying effects that were essential for differentiation. Taken together, these data reveal a novel metabolic role of TH in which this hormone regulates redox balance by inducing the transcription of Sod2 and by inducing a metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis.

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