Elevated Expression of Moesin in Muscular Dystrophies

Abstract

Fibrosis is the main complication of muscular dystrophies. We identified moesin, a member of the ezrin-radixin-moesin family, in dystrophic muscles of mice representing Duchenne and congenital muscular dystrophies (DMD and CMD, respectively) and dysferlinopathy, but not in the wild type. High levels of moesin were also observed in muscle biopsy specimens from DMD, Ullrich CMD, and merosin-deficient CMD patients, all of which present high levels of fibrosis. The myofibroblasts, responsible for extracellular matrix protein synthesis, and the macrophages infiltrating the dystrophic muscles were the source of moesin. Moesin-positive cells were embedded within the fibrotic areas between the myofibers adjacent to the collagen type I fibers. Radixin was also synthesized by the myofibroblasts, whereas ezrin colocalized with the myofiber membranes. In animal models and patients' muscles, part of the moesin was in its active phosphorylated form. Inhibition of fibrosis by halofuginone, an antifibrotic agent, resulted in a major decrease in moesin levels in the muscles of DMD and CMD mice. In summary, the results of this study may pave the way for exploiting moesin as a novel target for intervention in MDs, and as part of a battery of biomarkers to evaluate treatment success in preclinical studies and clinical trials.

Nintedanib decreases muscle fibrosis and improves muscle function in a murine model of dystrophinopathy

“…After muscle damage, activated fibroblasts gain migratory capabilities that allow them to move to the site of injury 29 , 30 . Using a scratch assay, we observed that nintedanib blocked cell migration promoted by PDGF-AA, bFGF, VEGF, and collagen tissue growth factor (CTGF) (Fig.…”

Two Sides of the Coin: Ezrin/Radixin/Moesin and Merlin Control Membrane Structure and Contact Inhibition

“…Consistent with a role in immunodeficiency, there are a number of reports linking moesin to roles in viral infection including measles [23], HIV [24] and hepatitis C [25]. Moesin has also been observed to have raised levels in muscular dystrophies [26], and cervical, breast and lung cancers [27,28,29].…”

The role of Nrf2 in acute and chronic muscle injury

“…Several studies have already outlined that the level of transforming growth factor (TGFβ-1), the main mediator of fibrosis, is increased in muscles and plasma of DMD patients (42). Similarly, collagen, the main component of fibrotic scar, has been elevated in muscles of murine (43) and canine (44) models of DMD, as well as in dystrophic patients (45). In our model, we have observed elevated mRNA level of Tgfb1 and Col1a1 not only in mdx mice but even at a higher degree in dystrophic mice additionally lacking transcriptionally active Nrf2, what is consistent with previous studies showing that Nrf2 acts as a protective agent against fibrosis in different tissues -lungs (46), pancreas (47), and kidney (48).…”