Nuclear Envelope Alterations in Myotonic Dystrophy Type 1 Patient-Derived Fibroblasts

Abstract

Myotonic dystrophy type 1 (DM1) is a hereditary and multisystemic disease characterized by myotonia, progressive distal muscle weakness and atrophy. The molecular mechanisms underlying this disease are still poorly characterized, although there are some hypotheses that envisage to explain the multisystemic features observed in DM1. An emergent hypothesis is that nuclear envelope (NE) dysfunction may contribute to muscular dystrophies, particularly to DM1. Therefore, the main objective of the present study was to evaluate the nuclear profile of DM1 patient-derived and control fibroblasts and to determine the protein levels and subcellular distribution of relevant NE proteins in these cell lines. Our results demonstrated that DM1 patient-derived fibroblasts exhibited altered intracellular protein levels of lamin A/C, LAP1, SUN1, nesprin-1 and nesprin-2 when compared with the control fibroblasts. In addition, the results showed an altered location of these NE proteins accompanied by the presence of nuclear deformations (blebs, lobes and/or invaginations) and an increased number of nuclear inclusions. Regarding the nuclear profile, DM1 patient-derived fibroblasts had a larger nuclear area and a higher number of deformed nuclei and micronuclei than control-derived fibroblasts. These results reinforce the evidence that NE dysfunction is a highly relevant pathological characteristic observed in DM1.

The Long-Term Culture of Human Fibroblasts Reveals a Spectroscopic Signature of Senescence

“…They have great advantages compared to other disease models, namely, their reproducibility and control of the study environment. Among the various types of cells, primary cultures of human fibroblasts, namely, dermal fibroblasts, have been extensively used as models of diseases [ 19 , 20 ]. Similar to all somatic cells, fibroblasts enter replicative senescence [ 21 ].…”

Nuclear envelope transmembrane proteins involved in genome organization are misregulated in myotonic dystrophy type 1 muscle

“…Despite all this information, it is still unclear which mechanism is contributing to which extent, and if yet unknown factors add to the development of this complex disease—especially in the different tissues affected. Intriguingly, alterations to the nuclear envelope (NE) structure and expression changes of NE transmembrane proteins (NETs) have been observed in primary DM1 myoblast and myotube cultures ( Hintze et al, 2018 ; Meinke et al, 2018 ) as well as in patient fibroblasts ( Rodríguez et al, 2015 ; Viegas et al, 2022 ). NE proteins are linked to a wide range of disorders, including myopathies and neuropathies.…”