Limb Girdle Muscular Dystrophy: An Interval Study of Weakness and Functional Impairment

Stübgen, Joerg‐Patrick

doi:10.1097/cnd.0b013e318163c5ba

Cited by 6 publications

(14 citation statements)

References 16 publications

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“…In clinical practice, progressive weakness and functional decline define the status and progression of disease and documents the natural course of myopathy (25,26,27,40). Although necrosis of muscle fiber represents the major cause of muscle weakness in muscular dystrophies (45), it is a late Values are expressed as means Ϯ SE.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…Patients with severe muscular dystrophies have limited opportunities to perform normal exercise protocols due to weakness . Anti‐gravity training in a lower body positive pressure (LBPP) chamber is a new training and rehabilitation modality which allows training during off‐lifting of body weight (BW) .…”

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confidence: 99%

Body weight-supported training in Becker and limb girdle 2I muscular dystrophy

et al. 2016

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“…Several genes that cause the disorders have been identified, but so far the identification of these gene/protein abnormalities has not changed patient care. Thus, because no curative genetic or pharmaceutical treatments are available, care is directed at the symptomatic impairments (Pandya et al, 2008; Stübgen, 2008).…”

Section: Introductionmentioning

confidence: 99%

Physiotherapy, based on the Bobath concept, may influence the gait pattern in persons with limb‐girdle muscle dystrophy: a multiple case series study

Oygard

Hæstad

Jørgensen

2011

Physiotherapy Res Intl

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Limb Girdle Muscular Dystrophy: An Interval Study of Weakness and Functional Impairment

Cited by 6 publications

References 16 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)

Body weight-supported training in Becker and limb girdle 2I muscular dystrophy

Physiotherapy, based on the Bobath concept, may influence the gait pattern in persons with limb‐girdle muscle dystrophy: a multiple case series study

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