Endocrine Abstracts

Fibro-adipogenic progenitors (FAPs), a muscle-resident stem cell population, have recently emerged as important actors of muscle regeneration by interacting with myogenic progenitors (MPs) to promote the formation of new muscle fibers. However, in pathological condition, as muscle dystrophies, this coordinated response is lost and then an accumulation of FAPs is observed. In particular, in a mouse model of Duchenne muscle dystrophy (mdx), the accumulation of a specific subpopulation of FAPs, named Vcam1 has been demonstrated. The reduction of Vcam1+ FAPs is associated with an improvement of muscle phenotype. We observed that thyroid hormone (TH) signaling is active in FAPs, that deiodinase type 3 is expressed specifically by Vcam1+ FAPs. We hypothesized that an intracellular hypothyroid state, assured by D3 expression, is a condition determining the Vicam1+ FAPs features. We found that D2, D3, thyroid hormone transporters and receptors, were expressed in FAPs thus suggesting that TH signal is active in this cell context. To verify if the D3 expression and the consequent hypothyroid status of Vicam1+ FAPs cells is a condition important for their expansion in a context of muscle dystrophy, we investigated the effects of Dio3 selective depletion in FAPs in Mdx mice. In mdx muscle from Dio3 depleted FAPs mice (D3KO-FAP), the number of Vicam1+FAPs cells was lower than what observed in control mice (D3WT-FAP, 288333 vs 131667 P = 0.028). Furthermore, the depletion of D3 in FAPs cells improved muscle phenotype. Cross sectional area of muscle fibers from D3KO-FAP mice were bigger than those from D3WT-FAP mice (2036 μm² vs 1780 μm² P = 0.022), whereas the extension of necrotic areas was smaller. The mRNA Pax7, MyoD, Myogenin and NeoMHC expression were higher in D3KO-FAP muscle than D3WT-FAP muscle, indicating that the D3 FAPs cells depletion enhances muscle regeneration. Interestingly, the mRNA expression of Myh2 and the number of MHCII positive fibers (a positive target gen of TH), were higher in D3KO-FAP than in D3WT-FAP (6,8% vs 10% P = 0.05). Taken together, these data show that TH signaling is active in FAPs and that D3 expression is required for the amplification of Vicam1+ FAPs cells. The reduction in Vicam1+ FAPs cells, induced by D3 depletion, improved muscle dystrophic phenotype. Our work could have numerous applications in muscle research for muscle dystrophies diseases, by providing a better understanding of the mechanisms underlying TH availability in the control of FAPs functions.