Myotonic Dystrophy—A Progeroid Disease?

Abstract

Myotonic dystrophies (DM) are slowly progressing multisystemic disorders caused by repeat expansions in the DMPK or CNBP genes. The multisystemic involvement in DM patients often reflects the appearance of accelerated aging. This is partly due to visible features such as cataracts, muscle weakness, and frontal baldness, but there are also less obvious features like cardiac arrhythmia, diabetes or hypogammaglobulinemia. These aging features suggest the hypothesis that DM could be a segmental progeroid disease. To identify the molecular cause of this characteristic appearance of accelerated aging we compare clinical features of DM to “typical” segmental progeroid disorders caused by mutations in DNA repair or nuclear envelope proteins. Furthermore, we characterize if this premature aging effect is also reflected on the cellular level in DM and investigate overlaps with “classical” progeroid disorders. To investigate the molecular similarities at the cellular level we use primary DM and control cell lines. This analysis reveals many similarities to progeroid syndromes linked to the nuclear envelope. Our comparison on both clinical and molecular levels argues for qualification of DM as a segmental progeroid disorder.

Nuclear Envelope Transmembrane Proteins in Myotonic Dystrophy Type 1

“…The most visible NE alterations are invaginations, which have been previously observed in DM1 fibroblasts (Rodriguez et al, 2015 ), and down-regulation of the lamins A and B1 (Meinke et al, 2018 ). We found a correlation between DMPK repeat length and the number of nuclei with NE invaginations (Meinke et al, 2018 ). With the aim to investigate which factors—apart from lamins—contribute to these structures, we screened a set of selected NE transmembrane proteins (NETs) for altered distribution in DM1 patients.…”

“…Based on our prior observation of NE alterations in DM1 myoblasts (Meinke et al, 2018 ), we investigated NETs regarding their expression and localization to explore their possible contribution to these structural changes. In myoblasts we found no localization changes for any of the investigated NETs (emerin, LBR, SUN1, SUN2, TMEM38a, TMEM70, nesprin 1, and nesprin 2).…”

“…DM1 patients had the following DMPK repeat lengths: DM1-1 240-430; DM1-2 400-600; DM1-3 1100-1300; DM1-4 1500. The patient cell lines used are identical to those where a repeat-length depending enrichment of nucleoplasmic reticuli was seen (Meinke et al, 2018 ).…”

“…Muscle differentiation defects have been described for DM1 (Furling et al, 2001 ; Mastroyiannopoulos et al, 2008 ), but it is unclear if the observed nuclear envelope alterations in DM1 myoblasts (Meinke et al, 2018 ) contribute to these defects in a similar manner as they do to nuclear envelope linked disease (Meinke and Schirmer, 2016 ). The most visible NE alterations are invaginations, which have been previously observed in DM1 fibroblasts (Rodriguez et al, 2015 ), and down-regulation of the lamins A and B1 (Meinke et al, 2018 ). We found a correlation between DMPK repeat length and the number of nuclei with NE invaginations (Meinke et al, 2018 ).…”

“…NETs have been linked to a wide range of disorders which include several myopathies (Meinke and Schirmer, 2016 ). In the light of the NE aberrations observed in DM1 myoblasts and myotubes (Meinke et al, 2018 ), NETs are possible candidates to contribute to DM1 muscle pathology. We decided to test the proteins emerin, LBR, TMEM38a, TMEM70, SUN1, SUN2, nesprin 1, and nesprin 2 for their localization and expression in primary DM1 myoblasts compared to controls.…”