Researchers uncovered the involvement of the platelet-derived growth factor AA (PDGF-AA) in the pathogenesis of Duchenne muscular dystrophy (DMD), as published in the Journal of Cachexia, Sarcopenia and Muscle.

The results demonstrate that PDGF-AA promotes the activation of the RhoA signaling pathway in skeletal muscle fibro-adipogenic progenitor cells (FAPs) derived from patients with DMD.

“This pathway could be involved in FAPs activation promoting its proliferation, migration, and actin reorganization, which represents the beginning of the fibrotic process,” the authors explained.


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They treated FAPs from 3 patients with DMD with PDGF-AA (50 ng/mL) and observed an increase in the expression of mediators of the RhoA signaling pathway when compared to untreated DMD-FAPs. Additional analysis showed that DMD muscles had a 7.7-fold increase in the levels of Rho guanine nucleotide exchange factor 2, an effector protein of the Rho-kinase pathway, compared to healthy controls.

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In vitro studies confirmed that PDGF-AA activates the RhoA/Rho-associated protein kinase 2 signaling pathway. This led to an increase in the proliferation and migration of FAPs. The PDGF-AA-mediated promoting effect was blocked by C3-exoenzyme and fasudil, 2 inhibitors of the RhoA signaling pathway.

The inhibitory effects of fasudil in the RhoA signaling pathway were further confirmed in a murine model of DMD. Moreover, fasudil treatment improved the performance of mice on grip strength test and decreased the amount of collagen type 1 and inflammatory markers.

“These results are in accordance with previous studies using fasudil as an antifibrotic agent as it has been shown that fasudil reduces collagen area, number of infiltrating macrophages and production of [transforming growth factor beta 1] and [connective tissue growth factor] in renal interstitial fibrosis induced by unilateral ureteral obstruction and in bleomycin-induced pulmonary fibrosis in mice,” the authors said.

They also observed an increase in the expression of proteins involved in other signaling cascades after treatment with PDGF-AA, including mitogen-activated protein kinase, PI3K-Akt, FoxO, and Hedgehog.

Reference

Fernández‐Simón E, Suárez‐Calvet X, Carrasco‐Rozas A, et al. RhoA/ROCK2 signalling is enhanced by PDGF‐AA in fibro‐adipogenic progenitor cells: implications for Duchenne muscular dystrophy. J Cachexia Sarcopenia Muscle. Published online February 7, 2022. doi:10.1002/jcsm.12923