Intracellular Inactivation of Thyroid Hormone Is a Survival Mechanism for Muscle Stem Cell Proliferation and Lineage Progression

Abstract

SummaryPrecise control of the thyroid hormone (T3)-dependent transcriptional program is required by multiple cell systems, including muscle stem cells. Deciphering how this is achieved and how the T3 signal is controlled in stem cell niches is essentially unknown. We report that in response to proliferative stimuli such as acute skeletal muscle injury, type 3 deiodinase (D3), the thyroid hormone-inactivating enzyme, is induced in satellite cells where it reduces intracellular thyroid signaling. Satellite cell-specific genetic ablation of dio3 severely impairs skeletal muscle regeneration. This impairment is due to massive satellite cell apoptosis caused by exposure of activated satellite cells to the circulating TH. The execution of this proapoptotic program requires an intact FoxO3/MyoD axis, both genes positively regulated by intracellular TH. Thus, D3 is dynamically exploited in vivo to chronically attenuate TH signaling under basal conditions while also being available to acutely increase gene programs required for satellite cell lineage progression.

Circulating follistatin displays a day–night rhythm and is associated with muscle mass and circulating leptin levels in healthy, young humans

“…This is consistent with the role of follistatin to increase muscle mass [2, 3]. This role could be the result of the regulation of follistatin by hormones such as thyroid hormones [21, 22] or other cytokines [23]. In our population, the correlation of follistatin levels with LBM was marginal and was lost after adjustment for BMI.…”

Coupling between Nutrient Availability and Thyroid Hormone Activation

“…A local role for D2-generated T 3 in skeletal muscle is less clear. The fact that skeletal muscle physiology is T 3 -sensitive (46) sets the stage for a potential D2 contribution, such as during development and response to injury (47). Nevertheless, selective D2 inactivation in the mouse skeletal muscle failed to identify a metabolic phenotype, and serum T 3 was preserved due to increased thyroidal T 3 production (48,49).…”

Cell death, clearance and immunity in the skeletal muscle

“…A fraction of proliferating satellite cells die, as assessed by positivity of the TUNEL assay and by the cleavage of poly ADP ribose polymerase, via a pathway involving the Foxo3 transcription factor. 51 Specific pathways have apparently been generated to modulate the ability of satellite cells to survive in response to various environmental stimuli including those related to the angiopoietin 1/Tie2 system, 52 to the member of the Melanomaassociated antigen D1 family of proteins, necdin, 53 and to the thyroid hormone. 51 FAPs comprise multipotent mesenchymal progenitor cells 54 that are a source of matrix-secreting activated myofibroblasts in the skeletal muscle.…”

“…51 Specific pathways have apparently been generated to modulate the ability of satellite cells to survive in response to various environmental stimuli including those related to the angiopoietin 1/Tie2 system, 52 to the member of the Melanomaassociated antigen D1 family of proteins, necdin, 53 and to the thyroid hormone. 51 FAPs comprise multipotent mesenchymal progenitor cells 54 that are a source of matrix-secreting activated myofibroblasts in the skeletal muscle. 55 Their fate appears to be finely regulated by the extent and by the characteristics of the inflammatory response (see below) and their regulated death and clearance is possibly critical to prevent tissue fibrosis.…”