Combinatorial activation of the WNT ‐dependent fibrogenic program by distinct complement subunits in dystrophic muscle

Abstract

Fibrosis is associated with compromised muscle functionality in Duchenne muscular dystrophy (DMD). We report observations with tissues from dystrophic patients and mice supporting a model to explain fibrosis in DMD, which relies on the crosstalk between the complement and the WNT signaling pathways and the functional interactions of two cellular types. Fibro‐adipogenic progenitors and macrophages, which populate the inflamed dystrophic muscles, act as a combinatorial source of WNT activity by secreting distinct subunits of the C1 complement complex. The resulting aberrant activation of the WNT signaling in responsive cells, such as fibro‐adipogenic progenitors, contributes to fibrosis. Indeed, pharmacological inhibition of the C1r/s subunits in a murine model of DMD mitigated the activation of the WNT signaling pathway, reduced the fibrogenic characteristics of the fibro‐adipogenic progenitors, and ameliorated the dystrophic phenotype. These studies shed new light on the molecular and cellular mechanisms responsible for fibrosis in muscular dystrophy and open to new therapeutic strategies. image In Duchenne muscular dystrophy patients, a chronic condition of inflammation and degeneration is determining a progressive substitution of muscle fibers by fibrotic extracellular matrix. Based on the following observations we propose the involvement of the complement C1 complex in this process. Complement C1 complex is locally produced in muscles of dystrophic mice and patients. Macrophages and fibro‐adipogenic progenitors (FAPs) are the primary cellular sources of C1qa/b/c/ and C1r/s, respectively. Macrophages and FAPs are increased and come in contact with each other in dystrophic muscle. The combination of C1qa/b/c/ and C1r/s is promoting the activation of the WNT signaling pathway. Pharmacological inhibition of C1r/s in dystrophic animal models reduces the WNT‐dependent fibrotic program in FAPs and alleviates dystrophy.