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RNA processing is altered in skeletal muscle nuclei of patients affected by myotonic dystrophy

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Abstract

Myotonic dystrophies (DMs) are characterised by highly variable clinical manifestations consisting of muscle weakness and atrophy, and a wide spectrum of extramuscular manifestations. In both DM1 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 for 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 an impairment of post-transcriptional pre-mRNA pathways. The transcription of the expanded sequences in DM myonuclei would therefore hamper functionality of the whole splicing machinery, slowing down the intranuclear molecular trafficking; this would reduce the capability of myonuclei to respond to anabolic stimuli thus contributing to muscle wasting.

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Acknowledgments

We express our gratitude to Prof. T.E. Martin for kindly providing us with the anti-hnRNP core protein antibody. Marzia Giagnacovo is a PhD student in receipt of a fellowship from the Dottorato di Ricerca in Biologia Cellulare (University of Pavia).

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Authors and Affiliations

  1. Dipartimento di Scienze Neurologiche, Neuropsicologiche, Morfologiche e Motorie, Sezione di Anatomia e Istologia, Università di Verona, Verona, Italy

    Manuela Malatesta

  2. Dipartimento di Biologia Animale, Laboratorio di Biologia cellulare e Neurobiologia, Università di Pavia, via Ferrata 1, 27100, Pavia, Italy

    Marzia Giagnacovo & Carlo Pellicciari

  3. Dipartimento di Biologia molecolare e Biotecnologie, Università degli Studi di Milano, Milan, Italy

    Rosanna Cardani

  4. Centro per lo Studio delle Malattie Neuromuscolari, CMN, Milan, Italy

    Rosanna Cardani

  5. Dipartimento di Neurologia, IRCCS Policlinico San Donato, Università degli Studi di Milano, Milan, Italy

    Giovanni Meola

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  1. Manuela Malatesta
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  2. Marzia Giagnacovo
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  3. Rosanna Cardani
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  4. Giovanni Meola
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  5. Carlo Pellicciari
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Correspondence to Carlo Pellicciari.

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Malatesta, M., Giagnacovo, M., Cardani, R. et al. RNA processing is altered in skeletal muscle nuclei of patients affected by myotonic dystrophy. Histochem Cell Biol 135, 419–425 (2011). https://doi.org/10.1007/s00418-011-0797-z

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