Sarcomeric dysfunction contributes to muscle weakness in facioscapulohumeral muscular dystrophy

Lassche, Saskia; Stienen, G. J. M.; Irving, Tom; Maarel, Silvère M. van der; Voermans, Nicol C.; Padberg, George W.; Granzier, Henk; Engelen, B.G.M. van; Ottenheijm, Coen A.C.

doi:10.1212/wnl.0b013e318282513b

Cited by 41 publications

(40 citation statements)

References 12 publications

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“…In contrast, tension developed by pure type 1 fibers, which prevail in soleus muscle, is not reduced in transgenic mice, consistent with the minimal force reduction observed in this muscle. This is consistent with the report that muscle fibers isolated from FSHD patients produced a significant force reduction, specifically involving fast-twitch fibers (22). Moreover, our analysis reveals a fast-to-slow shift in fiber-type composition in some FRG1 transgenic muscles.…”

Section: Discussionsupporting

confidence: 92%

“…Recent studies showed the selective reduction of force in type 2 muscle fibers from FSHD patients (22). This similarity with our findings in FRG1 transgenics, led us to investigate whether TNNT3 splicing profile can be correlated with clinical features such as muscle weakness or histological features found in FSHD patients.…”

Section: R131 Altered Troponin T Splicing In Fshdsupporting

confidence: 88%

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Altered Tnnt3 characterizes selective weakness of fast fibers in mice overexpressing FSHD region gene 1 (FRG1)

Sancisi

Germinario

Esposito

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

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cioscapulohumeral muscular dystrophy (FSHD), a common hereditary myopathy, is characterized by atrophy and weakness of selective muscle groups. FSHD is considered an autosomal dominant disease with incomplete penetrance and unpredictable variability of clinical expression within families. Mice overexpressing FRG1 (FSHD region gene 1), a candidate gene for this disease, develop a progressive myopathy with features of the human disorder. Here, we show that in FRG1-overexpressing mice, fast muscles, which are the most affected by the dystrophic process, display anomalous fast skeletal troponin T (fTnT) isoform, resulting from the aberrant splicing of the Tnnt3 mRNA that precedes the appearance of dystrophic signs. We determine that muscles of FRG1 mice develop less strength due to impaired contractile properties of fast-twitch fibers associated with an anomalous MyHC-actin ratio and a reduced sensitivity to Ca 2ϩ . We demonstrate that the decrease of Ca 2ϩ sensitivity of fast-twitch fibers depends on the anomalous troponin complex and can be rescued by the substitution with the wild-type proteins. Finally, we find that the presence of aberrant splicing isoforms of TNNT3 characterizes dystrophic muscles in FSHD patients. Collectively, our results suggest that anomalous TNNT3 profile correlates with the muscle impairment in both humans and mice. On the basis of these results, we propose that aberrant fTnT represents a biological marker of muscle phenotype severity and disease progression. muscular dystrophy; aberrant splicing; muscle weakness; FRG1; troponin T FACIOSCAPULOHUMERAL MUSCULAR dystrophy (FSHD), one of the three most common hereditary myopathies, presents progressive atrophy and weakness of a highly specific set of muscle groups (10,11,31). FSHD is characterized by insidious onset and unpredictable progression with high variability of clinical expression, even within the same family (36,37,42). At present, no molecular mechanisms have been implicated in the development of these disease phenotypes, and no biological markers are available to define and monitor disease expression.More than 50 genes have been associated with muscular dystrophies (MD), whose genetic defects have been molecularly defined, and numerous animal models have been developed (30). In many cases, invaluable insights into disease mechanisms, structure and function of gene products, and approaches for therapeutic interventions have benefited from the study of animal models of the different MDs (1). In this context, FSHD is unique because no mutations have been found in any protein-coding gene. Instead, FSHD has been associated with reduction of the number of tandemly repeated 3.3-kb DNA segments (named D4Z4 repeats) located at the subtelomeric region of chromosome 4q (2, 44, 48). The number of D4Z4 repeats varies from 11 to 150 in the general population, whereas less than 11 repeats are present in sporadic and familial FSHD patients (48). The current model to explain FSHD is that the reduction of D4Z4 repeats in FSHD subjects initiates in...

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Section: Discussionsupporting

confidence: 92%

Section: R131 Altered Troponin T Splicing In Fshdsupporting

confidence: 88%

Altered Tnnt3 characterizes selective weakness of fast fibers in mice overexpressing FSHD region gene 1 (FRG1)

Sancisi

Germinario

Esposito

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Since Type II fibers are the most commonly affected in Duchenne Muscular Dystrophy, it is thought that inducing the expression of Type I fibers will alleviate both the symptoms and progression of Duchenne Muscular Dystrophy. A similar trend was found in another type of muscular dystrophy, Facioscapulohumeral Muscular Dystrophy, as there is an early decrease in Type II fibers and an overall increase in the number of Type I fibers [29]. On the contrary, in myotonic dystrophy, Type I fibers are affected, as they atrophy more frequently and they lose a greater amount of force generation compared to Type II fibers [30][31][32].…”

Section: Muscular Dystrophiessupporting

confidence: 72%

Skeletal Muscle Fiber Types in Neuromuscular Diseases

Glaser¹,

Suzuki²

2018

Muscle Cell and Tissue - Current Status of Research Field

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In the human body, there are 600 individual skeletal muscles that allow us to perform a variety of functions such as executing locomotive tasks, breathing, and moving our eyes. The ratio of fiber types within the muscle critically contributes to determine the function of these muscles. Significant changes of muscle fiber types occur not only in normal development; changes have also been observed under abnormal conditions in neuromuscular disorders. In this review, we describe how muscle fiber types are specified during embryonic myogenesis, what potential factors are involved in the changes of fiber type composition, and how fiber type variations are influenced by the pathological conditions under specific neuromuscular disorders. Understanding skeletal muscle at the individual fiber level aids in studying the normal physiology and the pathology of disease in human.

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“…A pilot study in 4 FSHD muscle biopsies performed in our laboratory supports this hypothesis [19]. The present study aims to confirm these data in a larger cohort and elucidate the causes of sarcomeric dysfunction in FSHD.…”

Section: Introductionsupporting

confidence: 62%

Determining the role of sarcomeric proteins in facioscapulohumeral muscular dystrophy: a study protocol

et al. 2013

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BackgroundAlthough muscle weakness is a hallmark of facioscapulohumeral muscular dystrophy (FSHD), the molecular mechanisms that lead to weakness in FSHD remain largely unknown. Recent studies suggest aberrant expression of genes involved in skeletal muscle development and sarcomere contractility, and activation of pathways involved in sarcomeric protein degradation. This study will investigate the contribution of sarcomeric protein dysfunction to the pathogenesis of muscle weakness in FSHD.Methods/DesignEvaluation of sarcomeric function using skinned single muscle fiber contractile studies and protein analysis in muscle biopsies (quadriceps femoris and tibialis anterior) from patients with FSHD and age- and gender-matched healthy controls. Patients with other forms of muscular dystrophy and inflammatory myopathy will be included as disease controls to assess whether results are due to changes specific for FSHD, or a consequence of muscle disease in general. A total of 56 participants will be included. Extensive clinical parameters will be measured using MRI, quantitative muscle studies and physical activity assessments.DiscussionThis study is the first to extensively investigate muscle fiber physiology in FSHD following an earlier pilot study suggesting sarcomeric dysfunction in FSHD. The results obtained in this study will increase the understanding of the pathophysiology of muscle weakness in FSHD, and possibly identify novel targets for therapeutic intervention.

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Sarcomeric dysfunction contributes to muscle weakness in facioscapulohumeral muscular dystrophy

Cited by 41 publications

References 12 publications

Altered Tnnt3 characterizes selective weakness of fast fibers in mice overexpressing FSHD region gene 1 (FRG1)

Altered Tnnt3 characterizes selective weakness of fast fibers in mice overexpressing FSHD region gene 1 (FRG1)

Skeletal Muscle Fiber Types in Neuromuscular Diseases

Determining the role of sarcomeric proteins in facioscapulohumeral muscular dystrophy: a study protocol

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