Mitochondrial dysfunction in myotonic dystrophy type 1
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.
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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
References (42)
- et al.
The myotonic dystrophies: molecular, clinical, and therapeutic challenges
Lancet Neurol
(2012) - et al.
Differential signaling pathways following oxidative stress in mutant myotonin protein kinase cDNA-transfected C2C12 cell lines
Biochem Biophys Res Commun
(2000) - et al.
Brain magnetic resonance metabolic and microstructural changes in adult-onset autosomal dominant leukodystrophy
Brain Res Bull
(2015) - et al.
Magnetic resonance imaging and spectroscopy in the evaluation of neuromuscular disorders and fatigue
Neuromuscul Disord
(2012) - et al.
Relationship of white and gray matter abnormalities to clinical and genetic features in myotonic dystrophy type 1
NeuroImage Clin
(2016) - et al.
Basic principles of metabolic modeling of NMR (13)C isotopic turnover to determine rates of brain metabolism in vivo
Metab Eng
(2004) - et al.
Bioenergetics of skeletal muscle in mitochondrial myopathy
J Neurol Sci
(1994) - et al.
Non-invasive quantification of lactate by proton MR spectroscopy and its clinical applications
Clin Neurol Neurosurg
(2005) - et al.
Cortical surface-based analysis. I. Segmentation and surface reconstruction
Neuroimage
(1999) - et al.
Accurate, robust, and automated longitudinal and cross-sectional brain change analysis
Neuroimage
(2002)
Correlative MR imaging and 31P-MR spectroscopy study in sarcoglycan deficient limb girdle muscular dystrophy
Neuromuscul Disord
Coenzyme Q10, exercise lactate and CTG trinucleotide expansion in myotonic dystrophy
Brain Res Bull
Combined expression of tau and the Harlequin mouse mutation leads to increased mitochondrial dysfunction, tau pathology and neurodegeneration
Neurobiol Aging
Proton magnetic resonance spectroscopy of brain in congenital myotonic dystrophy
Pediatr Neurol
Correlation between CTG trinucleotide repeat length and frequency of severe congenital myotonic dystrophy
Nat Genet
Myotonic dystrophy: diagnosis, management and new therapies
Curr Opin Neurol
Myotonic dystrophy protein kinase (DMPK) prevents ROS-induced cell death by assembling a hexokinase II-Src complex on the mitochondrial surface
Cell Death Dis
Oxidative stress in myotonic dystrophy type 1
Free Radic Res
Central nervous system imaging in mitochondrial disorders
Can J Neurol Sci
A novel in-frame 18-bp microdeletion in MT-CYB causes a multisystem disorder with prominent exercise intolerance
Hum Mutat
Defective mitochondrial adenosine triphosphate production in skeletal muscle from patients with dominant optic atrophy due to OPA1 mutations
Arch Neurol
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Contributed equally.