Fibro-adipogenic progenitors (FAPs) are typically activated in response to muscle injury, and establish functional interactions with inflammatory and muscle stem cells (MuSCs) to promote muscle repair. We found that denervation causes progressive accumulation of FAPs, without concomitant infiltration of macrophages and MuSC-mediated regeneration. Denervation-activated FAPs exhibited persistent STAT3 activation and secreted elevated levels of IL-6, which promoted muscle atrophy and fibrosis. FAPs with aberrant activation of STAT3-IL-6 signalling were also found in mouse models of spinal cord injury, spinal muscular atrophy, amyotrophic lateral sclerosis (ALS) and in muscles of ALS patients. Inactivation of STAT3-IL-6 signalling in FAPs effectively countered muscle atrophy and fibrosis in mouse models of acute denervation and ALS (SOD mice). Activation of pathogenic FAPs following loss of integrity of neuromuscular junctions further illustrates the functional versatility of FAPs in response to homeostatic perturbations and suggests their potential contribution to the pathogenesis of neuromuscular diseases.

Skeletal muscle is composed of a large and heterogeneous assortment of cell populations that interact with each other to maintain muscle homeostasis and orchestrate regeneration. Although satellite cells (SCs) – which are muscle stem cells – are the protagonists of functional muscle repair following damage, several other cells such as inflammatory, vascular, and mesenchymal cells coordinate muscle regeneration in a finely tuned process. Fibro–adipogenic progenitors (FAPs) are a muscle interstitial mesenchymal cell population, which supports SCs differentiation during tissue regeneration. During the first days following muscle injury FAPs undergo massive expansion, which is followed by their macrophage-mediated clearance and the re-establishment of their steady-state pool. It is during this critical time window that FAPs, together with the other cellular components of the muscle stem cell niche, establish a dynamic network of interactions that culminate in muscle repair. A number of different molecules have been recently identified as important mediators of this cross-talk, and its alteration has been associated with different muscle pathologies. In this review, we will focus on the soluble factors that regulate FAPs activity, highlighting their roles in orchestrating the inter-cellular interactions between FAPs and the other cell populations that participate in muscle regeneration.

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