Abstract
Cellular adhesion and migration are key functions that are disrupted in numerous diseases. We report that desmin, a type-III muscle-specific intermediate filament, is a novel cell adhesion regulator. Expression of p.R406W mutant desmin, identified in patients with desmin-related myopathy, modified focal adhesion area and expression of adhesion-signaling genes in myogenic C2C12 cells. Satellite cells extracted from desmin-knock-out (DesKO) and desmin-knock-in-p.R405W (DesKI-R405W) mice were less adhesive and migrated faster than those from wild-type mice. Moreover, we observed mislocalized and aggregated vinculin, a key component of cell adhesion, in DesKO and DesKI-R405W muscles. Vinculin expression was also increased in desmin-related myopathy patient muscles. Together, our results establish a novel role for desmin in cell-matrix adhesion, an essential process for strength transmission, satellite cell migration and muscle regeneration. Our study links the patho-physiological mechanisms of desminopathies to adhesion/migration defects, and may lead to new cellular targets for novel therapeutic approaches.
Highlights
The cytoskeleton orchestrates many essential cell processes such as cellular division, mechanosensing, adhesion and motility
Two bands corresponding to endogenous and exogenous desmin were revealed with antidesmin specific antibodies, allowing us to quantify the ratio between the two forms
As previously reported (Delort et al, 2019), endogenous desmin was always more highly expressed than exogenous desmin (Figure 1A, the ratio of exogenous/ endogenous varies from 0.1 to 0.7), corresponding to moderate desmin overexpression close to the pathophysiological conditions observed in patients
Summary
The cytoskeleton orchestrates many essential cell processes such as cellular division, mechanosensing, adhesion and motility. These functions derive from the three main structural networks: microfilaments (actin filaments), microtubules and intermediate filaments (IFs). Most studies focus on the role of microfilament or microtubule networks in cell adhesion and migration. New insights indicate an important role of the IF family in various cell types such as myoblasts (Etienne-Manneville, 2018; Agnetti et al, 2021; Kural Mangit et al, 2021). The cell-specific IF network is often pictured as an integrator of microfilaments and microtubules via a complex set of cross-bridging proteins (Seifert et al, 1992).
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