Mitochondrial dysfunction in myotonic dystrophy type 1

Laura Ludovica Gramegna, Maria Pia Giannoccaro, David Neil Manners, Claudia Testa, Stefano Zanigni, Stefania Evangelisti, Claudio Bianchini, Federico Oppi, Roberto Poda, Patrizia Avoni, Raffaele Lodi, Rocco Liguori, Caterina Tonon

Research output: Contribution to journalArticle

Abstract

The pathophysiological mechanism linking the nucleotide expansion in the DMPK gene to the clinical manifestations of myotonic dystrophy type 1 (DM1) is still unclear. In vitro studies demonstrate DMPK involvement in the redox homeostasis of cells and the mitochondrial dysfunction in DM1, but in vivo investigations of oxidative metabolism in skeletal muscle have provided ambiguous results and have never been performed in the brain. Twenty-five DM1 patients (14M, 39 ± 11years) underwent brain proton MR spectroscopy (1H-MRS), and sixteen cases (9M, 40 ± 13 years old) also calf muscle phosphorus MRS (31P-MRS). Findings were compared to those of sex- and age-matched controls. Eight DM1 patients showed pathological increase of brain lactate and, compared to those without, had larger lateral ventricles (p < 0.01), smaller gray matter volumes (p < 0.05) and higher white matter lesion load (p < 0.05). A reduction of phosphocreatine/inorganic phosphate (p < 0.001) at rest and, at first minute of exercise, a lower [phosphocreatine] (p = 0.003) and greater [ADP] (p = 0.004) were found in DM1 patients compared to controls. The post-exercise indices of muscle oxidative metabolism were all impaired in DM1, including the increase of time constant of phosphocreatine resynthesis (TC PCr, p = 0.038) and the reduction of the maximum rate of mitochondrial ATP synthesis (p = 0.033). TC PCr values correlated with the myotonic area score (ρ = 0.74, p = 0.01) indicating higher impairment of muscle oxidative metabolism in clinically more affected patients. Our findings provide clear in vivo evidence of multisystem impairment of oxidative metabolism in DM1 patients, providing a rationale for targeted treatment enhancing energy metabolism.

Original languageEnglish
Pages (from-to)144-9
JournalNeuromuscular Disorders
Volume28
DOIs
Publication statusPublished - 2018

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Myotonic Dystrophy
Phosphocreatine
Muscles
Brain
Exercise
Lateral Ventricles
Adenosine Diphosphate
Phosphorus
Energy Metabolism
Oxidation-Reduction
Protons
Lactic Acid
Skeletal Muscle
Homeostasis
Magnetic Resonance Spectroscopy
Nucleotides
Adenosine Triphosphate
Phosphates
Genes

Keywords

  • Journal Article

Cite this

Gramegna, L. L., Giannoccaro, M. P., Manners, D. N., Testa, C., Zanigni, S., Evangelisti, S., ... Tonon, C. (2018). Mitochondrial dysfunction in myotonic dystrophy type 1. Neuromuscular Disorders, 28, 144-9. https://doi.org/10.1016/j.nmd.2017.10.007

Mitochondrial dysfunction in myotonic dystrophy type 1. / Gramegna, Laura Ludovica; Giannoccaro, Maria Pia; Manners, David Neil; Testa, Claudia; Zanigni, Stefano; Evangelisti, Stefania; Bianchini, Claudio; Oppi, Federico; Poda, Roberto; Avoni, Patrizia; Lodi, Raffaele; Liguori, Rocco; Tonon, Caterina.

In: Neuromuscular Disorders, Vol. 28, 2018, p. 144-9.

Research output: Contribution to journalArticle

Gramegna, LL, Giannoccaro, MP, Manners, DN, Testa, C, Zanigni, S, Evangelisti, S, Bianchini, C, Oppi, F, Poda, R, Avoni, P, Lodi, R, Liguori, R & Tonon, C 2018, 'Mitochondrial dysfunction in myotonic dystrophy type 1', Neuromuscular Disorders, vol. 28, pp. 144-9. https://doi.org/10.1016/j.nmd.2017.10.007
Gramegna LL, Giannoccaro MP, Manners DN, Testa C, Zanigni S, Evangelisti S et al. Mitochondrial dysfunction in myotonic dystrophy type 1. Neuromuscular Disorders. 2018;28:144-9. https://doi.org/10.1016/j.nmd.2017.10.007
Gramegna, Laura Ludovica ; Giannoccaro, Maria Pia ; Manners, David Neil ; Testa, Claudia ; Zanigni, Stefano ; Evangelisti, Stefania ; Bianchini, Claudio ; Oppi, Federico ; Poda, Roberto ; Avoni, Patrizia ; Lodi, Raffaele ; Liguori, Rocco ; Tonon, Caterina. / Mitochondrial dysfunction in myotonic dystrophy type 1. In: Neuromuscular Disorders. 2018 ; Vol. 28. pp. 144-9.
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AU - Zanigni, Stefano

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