Type 2 deiodinase promotes fatty adipogenesis in muscle fibroadipogenic progenitors from adult male mice.

Fibro-adipogenic progenitor cells (FAPs) are a heterogeneous population of multipotent mesenchymal cells that give rise to fibroblasts and adipocytes. In response to muscle injury, FAPs are activated and cooperate with inflammatory and muscle stem cells to promote muscle regeneration. In pathological conditions, such as muscular dystrophies, this coordinated response is partially lost and an accumulation of FAPs is observed which is responsible for a maladaptive fibrosis, ectopic fat deposition and impaired muscle regeneration. The role of intracellular thyroid hormone (TH) signaling in this cellular context is largely unknown. Here we show that intracellular T3 concentration in FAPs is increased in vitro during adipogenic differentiation via the increase of the T3-producing type 2 deiodinase (D2). The adipogenic potential is reduced in FAPs cultured in the presence of rT3, a specific D2 inhibitor, while exogenous administration of THs is able to induce the expression of relevant adipogenic genes. Accordingly, upon genetic D2 depletion in vivo, adipogenesis was significantly reduced in D2KO compared to control mice. These data were confirmed using a FAP-inducible specific D2-KO mouse model, suggesting that a cell-specific D2-depletion in FAPs is sufficient to decrease fatty muscle infiltration and to improve muscle regeneration. Taken together, these data show that TH signaling is dynamically modulated in FAPs wherein D2-produced T3 is required to promote maturation of FAPs into adipocytes.