Mitochondrial dysfunction in myotonic dystrophy type 1

Author:

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  

Journal:

NEUROMUSCULAR DISORDERS

Issue Date:

2018

Abstract(summary):

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 +/- 11 years) underwent brain proton MR spectroscopy (H-1-MRS), and sixteen cases (9M, 40 +/- 13 years old) also calf muscle phosphorus MRS (P-31-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 =3D 0.003) and greater [ADP] (p =3D 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 =3D 0.038) and the reduction of the maximum rate of mitochondrial ATP synthesis (p =3D 0.033). TC PCr values correlated with the myotonic area score (p =3D 0.74, p =3D 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. (C) 2017 Elsevier B.V. All rights reserved.

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