Intrinsic Myogenic Potential of Skeletal Muscle-Derived Pericytes from Patients with Myotonic Dystrophy Type 1
C. Rosanne M. AusemsRenée H.L. RaaijmakersWalterus Johannes Antonius Adriana van den BroekMarieke WillemseBaziel G.M. van EngelenDerick G. WansinkHans van Bokhoven
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Abstract:
Pericytes are multipotent, vessel-associated progenitors that exhibit high proliferative capacity, can cross the blood-muscle barrier, and have the ability to home to muscle tissue and contribute to myogenesis. Consequently, pericyte-based therapies hold great promise for muscular dystrophies. A complex multi-system disorder exhibiting muscular dystrophy for which pericytes might be a valuable cell source is myotonic dystrophy type 1 (DM1). DM1 is caused by an unstable (CTG)n repeat in the DMPK gene and characterized by skeletal muscle weakness, muscle wasting, and myotonia. We have successfully isolated alkaline phosphatase-positive pericytes from skeletal muscle of DM1 patients and a transgenic mouse model. Intranuclear (CUG)n RNA foci, a pathogenic DM1 hallmark, were identified in human and mouse pericytes. Notably, pericytes from DM1 patients maintained similar growth parameters and innate myogenic characteristics in vitro compared to cells from unaffected controls. Our in vitro results thus demonstrate the potential of pericytes to ameliorate muscle features in DM1 in a therapeutic setting.Keywords:
Pericyte
ITGA7
Muscle weakness
ABSTRACT Introduction : The objective of this study was to develop a simple method for quantitative assessment of myotonia in patients with myotonic dystrophy type 1 (DM1) and DM2, to compare the myotonia severity, and to correlate this objective outcome with a subjective scale, the Myotonia Behaviour Scale (MBS). Methods : A commercially available dynamometer was used for all measurements. The relaxation time after voluntary contraction was measured in 20 patients with DM1, 25 patients with DM2, and 35 healthy controls. Results : The average relaxation time was 0.17 s in controls, 2.96 s in patients with DM1, and 0.4 s in patients with DM2. The correlation between relaxation time and MBS score was significant, 0.627 in patients with DM1 and 0.581 in patients with DM2. Discussion : Our method provides a valid and reliable quantitative measure of grip myotonia suitable as an outcome measure in clinical trials and as part of routine examinations to gather data on the natural history of myotonic disorders. Muscle Nerve 59:431–435, 2019
Muscle relaxation
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Myotonic dystrophy type 1 (DM1) is an autosomal-dominant disorder related to expansion of a CTG repeat in the gene for DM protein kinase (DMPK) from the normal 5 to 37 repeats to between 50 and 4000 repeats. A second form of myotonic dystrophy, DM type 2 (DM2), is associated with a CCTG repeat expansion in the gene for zinc finger 9 (ZNF9). Myotonia involving various muscles, and typically the intrinsic hand muscles and the flexors of the fingers, is a common manifestation of myotonic dystrophies.
To assess the feasibility of quantifying hand-muscle …
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Twenty-five successive patients with myotonic dystrophy were examined to determine the anatomical distribution of electrical myotonia. Proximal and distal limb muscles and orbicularis oris and masseter muscles were examined. Electrical myotonia was present in all muscles examined in only 3 patients. Moreover, of the 15 muscles examined, none showed myotonic discharges in every patient, the highest individual muscle involvement being 96%.
Myotonia congenita
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In myotonic dystrophy type 1, several studies have suggested causal relationships between CTG repeat length and the severity of symptoms, such as weakness or myotonia. We aimed to explore these relationships in a large population of 144 DM1 patients. All patients underwent clinical and functional assessments using a standardized test for grip strength and myotonia assessment. Myotonia was assessed using a fully automatic software based on mathematical modeling of relaxation force curve. CTG repeat length was statistically correlated with both myotonia and grip strength, which are two major primary neuromuscular symptoms of DM1 patients. However, these relationships are not clinically meaningful and not predictive at the individual level.
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Muscle weakness
Muscle disease
Neuromuscular disease
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Myotonia congenita
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Дистрофическая миотония это генетически детерминированное нервно-мышечное заболевание, относящееся к каналопатиям (заболеваниям, связанным с патологией ионных каналов мембран скелетных мышечных волокон). Классическими признаками миотонии являются миотонические феномены, характеризующиеся замедленным расслаблением скелетных мышц после произвольного сокращения или электрической стимуляции и миотоническими разрядами, выявляемые при клиническом обследовании и игольчатой электромиографии соответственно. Типичным представителем является миотоническая дистрофия (или дистрофическая миотония), описанная в начале прошлого века несколькими авторами и получившая название болезни Россолимо Штейнерта Куршмана. Данная нозологическая единица является самым распространенным заболеванием из разряда миотоний и самой частой формой мышечной дистрофии у взрослых людей. Миотония может вовлекать все группы мышц. Однако характер поражения мышц может варьировать в зависимости от конкретного заболевания. В статье описаны этиология, патогенез, формы, диагностика и основные принципы лечения. Описан клинический случай. Dystrophic myotonia is a genetically determined neuromuscular disease related to canalopathies (diseases associated with the pathology of the ion channels of the skeletal muscle fiber membranes). Classic signs of myotonia are myotonic phenomena characterized by delayed relaxation of skeletal muscles after arbitrary contraction or electrical stimulation and myotonic discharges detected during clinical examination and needle electromyography, respectively. A typical representative is myotonic dystrophy (or dystrophic myotonia), described at the beginning of the last century by several authors and called Rossolimo-Steinert-Kurschmann disease. This nosological unit is the most common disease of the category of myotonia and the most common form of muscular dystrophy in adults. Myotonia can involve all muscle groups. However, the nature of muscle damage may vary depending on the specific disease. The article describes the etiology, pathogenesis, forms, diagnosis, and basic principles of treatment. A clinical case is described.
Myotonia congenita
Neuromuscular disease
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Abstract The myotonic dystrophies can be considered as clinical syndromes that include subtypes designated as myotonic dystrophy type 1 (DMI) and myotonic dystrophy type 2 (DM2), each of which is determined by a distinct genetic locus (Meola 2000). It is possible that further specific subtypes will be identified, and these will be designated DM3, etc. This nomenclature was recommended by an international panel (Ashizawa 2000) and is followed in this chapter. Alternatively, some experts reserve the term ‘myotonic dystrophy’ (myotonia atrophica, dystrophia myotonica, myotonic muscular dystrophy) for the monogenic disorder, in which a characteristic pattern of dystrophic muscle disease is accompanied by myotonia and by specific abnormalities of other systems, originally described by Steinert, and prefer a different designation for variants that are clinically and genetically distinct, such as proximal myotonic myopathy (PROMM).
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