Endocrine Abstracts

Thyroid hormone (TH) is a major determinant of muscle physiology, and thyroid dysfunctions are leading causes of many myopathies. Precise control of thyroid hormone-dependent transcription is required by multiple cell system, including muscle stem cells, but how this is achieved is still largely unknown. Intracellular TH concentration is determined by a metabolic balance between the activating and inactivating deiodinase enzymes, D2 and D3. In functional combinations, these regulatory enzymes provide the ability to fine tune TH action at cellular level.

We demonstrated that D2-induced T₃ production is essential for normal myogenesis and muscle regeneration and that mice lacking D2 fail in their regeneration process. D3 − the TH inactivating enzyme− is an oncofetal protein frequently re−expressed during the adult life in proliferating tissues. In addition to D3’s expression in embryonic tissues and tumors, D3 can also be reactivated in response to diverse tissue injuries, which include myocardial infarction and hypertrophic cardiac failure, inflammation liver regeneration and neural injury. We recently demonstrated a novel role of the TH inactivation by D3 in muscle stem cells (satellite cells) and in muscle regeneration. Our data demonstrate that in response to proliferative stimuli such as skeletal muscle acute injury, D3 is specifically induced in satellite cells where it reduces intracellular thyroid signaling. Satellite-specific genetic ablation of D3 impairs skeletal muscle regeneration. This impairment is due to massive satellite cell apoptosis, caused by aberrant exposure of activated satellite cells to the physiological, but spatio-temporally excessive, TH concentrations in the circulation. In conclusion, our results indicate that the D2 and D3 enzymes are dynamically exploited in vivo to adapt TH-signaling and simultaneously orchestrate distinct gene activation and repression programs required for the satellite cell lineage progression and survival.

These studies suggest that the selective modulation of thyroid hormone concentration could be used to enhance rate-limiting steps in the muscle regeneration process, modulating stem cells expansion and/or differentiation, this might contribute to optimizing