Elsevier

Neuromuscular Disorders

Volume 28, Issue 2, February 2018, Pages 144-149
Neuromuscular Disorders

Mitochondrial dysfunction in myotonic dystrophy type 1

https://doi.org/10.1016/j.nmd.2017.10.007Get rights and content

Highlights

  • Brain 1H-MRS showed pathological lactate accumulation in one third of DM1 patients.

  • Lactate was higher in DM1 with higher white matter lesion load and cortical atrophy.

  • Muscle 31P-MRS showed oxidative mitochondrial metabolism deficits in DM1.

  • Muscle mitochondrial ATP production was slower in more clinically affected DM1.

  • In vivo multi-organ evidence of oxidative metabolism deficit in DM1 was provided.

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.

Introduction

Myotonic dystrophy type 1 (DM1) is the most common form of autosomal dominant muscular dystrophy due to an expansion of an unstable CTG-repeat in the 3'-untranslated region of the myotonic dystrophy protein kinase (DMPK) gene [1]. Based on triplet expansion, four categories (E1-E4) are distinguished, and related to the severity of clinical presentation [2].

To link the nucleotide expansion in the DMPK gene to the multisystem involvement characterizing the DM1 adult form, several pathophysiological hypotheses have been developed [3]. Among them, robust evidence suggests that mitochondrial dysfunction is crucial in the pathophysiology of DM1. In vitro studies attested the role of DMPK in the cell's redox homeostasis [4], and an increased susceptibility to oxidative stress in a model of CTG repeat in the myotonin protein kinase gene [5]. Moreover, signs of mitochondrial alteration in muscle biopsy and plasmatic markers of oxidative stress have been detected in DM1 patients [6].

Proton MR spectroscopy (1H-MRS) is a non-invasive technique sensitive to in vivo brain oxidative metabolism, detecting pathological accumulation of lactate (Lac) in primary [7] or secondary mitochondrial oxidative impairment [8]. Similarly, phosphorous MRS (31P-MRS) is able to detect in vivo skeletal muscle impairment of oxidative mitochondrial metabolism due to mitochondrial DNA mutations [9], [10] or other genetic neurodegenerative disorders [11], [12]. Results of previous skeletal muscle 31P-MRS studies of DM patients without molecular confirmation were ambiguous, in that impairment of mitochondrial oxidative metabolism was detected in the forearm flexor digitorum muscles but not in the calf muscles [13].

We investigated the role of mitochondrial dysfunction in the pathogenesis of DM1 by assessing in vivo skeletal muscle and brain oxidative metabolism using proton and phosphorus MRS.

Section snippets

Subjects

Twenty-five DM1 patients (14 males and 11 females, mean age ± SD = 39 ± 11 years, range = 22–71years), twenty-four part of a previous neuroimaging study [14], were recruited from the IRCCS Institute of Neurological Sciences of Bologna (Table 1). Genetic diagnosis was performed quantifying the size of CTG repeats in peripheral leucocytes [2].

Clinical evaluation, including the MRC calf muscle strength score [15], the Muscular Impairment Rating Scale (MIRS) score [16] and the DM1 functional scale

Demographical and clinical

All DM1 patients underwent brain 1H-MRS, 16 patients performed calf muscle 31P-MRS examination at rest, and 11 of them were able to perform an aerobic exercise of adequate intensity.

Patients' clinical profile is reported in Table 1. One patient presented a congenital onset, 10 an infantile/juvenile onset, 12 adult onset and 2 were asymptomatic. Four patients [3M, mean (SD) age = 45(17) years] were classed as category E1 (50–150 CTG repeats), fourteen [7M, 37(10) years] as category 2 (150–1000

Discussion

In vivo skeletal muscle and brain energy metabolism was investigated in genetically determined DM1 patients. Skeletal muscle 31P-MRS in DM1 patients showed that during initial exercise the degree of calf muscle energy metabolism impairment correlated with age at disease onset, and during post-exercise recovery correlated with myotonia severity. 1H-MRS detected a pathological CSF accumulation of Lac in 1/3 of DM1 patients who showed larger lateral ventricle and smaller gray matter volumes, and

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