MYOFIBRILLAR AND DISTAL MYOPATHIES: P.253Severe intestinal pseudo-obstruction in a p.R405W desmin knock-in model: a new phenotype lead to light smooth muscle involvement in myofibrillar myopathies

Abstract

The intermediate filament desmin, specifically expressed in striated and smooth muscle cells, forms a filament network which provides maintenance of cellular integrity, resistance to mechanical stress, force transmission and mechanochemical signaling. Abnormal expression or lack of desmin leads to a progressive disruption of the contractile machinery, which can be observed in the muscles from patients affected by myofibrillar myopathies (MFM) due to mutations of the desmin gene DES (DES-MFM). To clarify the pathophysiology of DES-MFM, we generated a mouse KI model expressing the R405W DES mutation, homologous to human R406W. This mutation is associated with a severe and relatively early clinical phenotype in patients, which develop muscular weakness, cardiopathy and respiratory failure from the third decade of life. Molecular studies showed that p.Arg406Trp desmin has a reduced ability to support longitudinal annealing as well as radial compaction, two essential steps required for the formation of the desmin network. Heterogygous DesWT/R405W as well as homozygous DesR405W/R405W KI mice showed abnormal accumulation of desmin at the subsarcolemmal membrane in striated muscles. Homozygous animals died early (at 3.4 ± 1.2 months) and developed severe dilatation of the intestinal tract associated with food stasis in the lumen around 3 months. Echographic and histological studies showed a thickening of the colon and desmin aggregates in all muscle segments of the digestive tract. Functional studies revealed reduced spontaneous contraction and strength generation of the homozygous duodenum, suggesting an alteration of the mechanical properties of smooth muscle cells. Intestinal malapsorption and pseudo-obstruction have been reported in very rare DES-MFM patients. Our model brings to light the importance of desmin for intestinal smooth muscles, and suggests that smooth muscle involvement may have been underestimated in patients suffering from MFMs.