| Summary: | Myotonic dystrophies (DMs) have highly variable clinical manifestations consisting in muscle weakness and atrophy, and a wide spectrum of extramuscular manifestations. In both DMl and DM2 forms, expanded nucleotide sequences cause the accumulation of mutant transcripts in the nucleus, thus deregulating the function of some RNA-binding proteins and providing a plausible explanation for the multifactorial phenotype of DM patients. However, at the skeletal muscle level, no mechanistic explanation tor the muscle wasting has so far been proposed. We therefore performed a study in situ by immunoelectron microscopy on biceps brachii biopsies from DM1, DM2 and healthy subjects, providing the first ultrastructural evidence on the distribution of some nuclear ribonucleoprotein (RNP)-containing structures and molecular factors involved in pre-mRNA transcription and maturation in dystrophic myonuclei. Our results demonstrated an accumulation of splicing and cleavage factors in myonuclei of both DM1 and DM2 patients, suggesting that the transcription of the expanded sequences in DM myonuclei would impair the post-transcriptional pre-mRNA pathways, and hamper functionality of the whole splicing machinery, slowing down the intranuclear molecular trafficking. Interestingly, this has been found to occur in different tissues, including skeletal muscle, of old rodents DM muscle seems therefore lo share similarities with the ageing muse le which is also characterised by loss of mass, strength and function, thus encouraging comparative studies tor the detection of common cellular mechanisms at the basis of skeletal muscle wasting in ageing and DMs
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