Fig. 8.

FAPs control the onset and severity of disease in LGMD2B. a Healthy and/or pre-symptomatic LGMD2B muscle contains resident FAPs. b After myofiber injury, inflammatory cells invade and trigger FAP proliferation. Successful regeneration involves a switch between pro-inflammatory and pro-regenerative signaling, causing the removal of inflammatory cells and FAPs. c In symptomatic LGMD2B muscle, there is a gradual accumulation of extracellular AnxA2, which prolongs the pro-inflammatory environment, causing excessive FAP proliferation. This cellular niche becomes pro-adipogenic over time, allowing for differentiation of FAPs and the adipogenic conversion of muscle. d Blocking aberrant signaling due to AnxA2 buildup blocks FAP accumulation and thus preventing adipogenic loss of dysferlinopathic muscle. Similarly, use of a MMP-14 inhibitor (Batimastat) inhibits FAP adipogenesis offering a potential drug-based therapy to prevent adipogenic loss of dysferlinopathic muscle