Dataset Information

Don't forget the trunk in Duchenne muscular dystrophy patients: more muscle weakness and compensation than expected.

ABSTRACT: BACKGROUND:Performing daily activities independently becomes more difficult in time for patients with Duchenne muscular dystrophy (DMD) due to muscle weakness. When performing seated daily activities, the trunk plays an indispensable role besides the upper extremities. However, knowledge is lacking on the interaction between trunk and upper extremities. Therefore the aim was to investigate whether patients with DMD use trunk movement to compensate for reduced arm function when performing seated tasks, and whether this is related to increased muscle activity. METHODS:Eighteen boys with DMD and twenty-five healthy controls (HC) performed several tasks when sitting unsupported, like reaching (and placing) forward and sideward, drinking and displacing a dinner plate. Maximum joint torque and maximum surface electromyography (sEMG) were measured during maximum voluntary isometric contractions. Three-dimensional movements and normalized sEMG when performing tasks were analyzed. RESULTS:Significantly decreased maximum joint torque was found in DMD patients compared to HC. Trunk and shoulder torques were already decreased in early disease stages. However, only maximum trunk rotation and shoulder abduction torque showed a significant association with Brooke scale. In all reaching and daily tasks, the range of motion in lateral bending and/or flexion-extension was significantly larger in DMD patients compared to HC. The trunk movements did not significantly increase with task difficulty (e.g. increasing object weight) or Brooke scale. Normalized muscle activity was significantly higher in DMD patients for all tasks and muscles. CONCLUSIONS:Boys with DMD use increased trunk movements to compensate for reduced arm function, even when performing relatively simple tasks. This was combined with significantly increased normalized muscle activity. Clinicians should take the trunk into account when assessing function and for intervention development, because DMD patients may appear to have a good trunk function, but percentage of muscle capacity used to perform tasks is increased.

SUBMITTER: Peeters LHC

PROVIDER: S-EPMC6437973 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Don't forget the trunk in Duchenne muscular dystrophy patients: more muscle weakness and compensation than expected.

Peeters L H C LHC Kingma I I van Dieën J H JH de Groot I J M IJM

Journal of neuroengineering and rehabilitation 20190327 1

<h4>Background</h4>Performing daily activities independently becomes more difficult in time for patients with Duchenne muscular dystrophy (DMD) due to muscle weakness. When performing seated daily activities, the trunk plays an indispensable role besides the upper extremities. However, knowledge is lacking on the interaction between trunk and upper extremities. Therefore the aim was to investigate whether patients with DMD use trunk movement to compensate for reduced arm function when performing ...[more]

PMID: 30917845

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Project description:Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy caused by mutations in the dystrophin gene. Loss of dystrophin initiates a progressive decline in skeletal muscle integrity and contractile capacity which weakens respiratory muscles including the diaphragm, culminating in respiratory failure, the leading cause of morbidity and mortality in DMD patients. At present, corticosteroid treatment is the primary pharmacological intervention in DMD, but has limited efficacy and adverse side effects. Thus, there is an urgent need for new safe, cost-effective, and rapidly implementable treatments that slow disease progression. One promising new approach is the amplification of nitric oxide-cyclic guanosine monophosphate (NO-cGMP) signalling pathways with phosphodiesterase 5 (PDE5) inhibitors. PDE5 inhibitors serve to amplify NO signalling that is attenuated in many neuromuscular diseases including DMD. We report here that a 14-week treatment of the mdx mouse model of DMD with the PDE5 inhibitor sildenafil (Viagra(®), Revatio(®)) significantly reduced mdx diaphragm muscle weakness without impacting fatigue resistance. In addition to enhancing respiratory muscle contractility, sildenafil also promoted normal extracellular matrix organization. PDE5 inhibition slowed the establishment of mdx diaphragm fibrosis and reduced matrix metalloproteinase-13 (MMP-13) expression. Sildenafil also normalized the expression of the pro-fibrotic (and pro-inflammatory) cytokine tumour necrosis factor ? (TNF?). Sildenafil-treated mdx diaphragms accumulated significantly less Evans Blue tracer dye than untreated controls, which is also indicative of improved diaphragm muscle health. We conclude that sildenafil-mediated PDE5 inhibition significantly reduces diaphragm respiratory muscle dysfunction and pathology in the mdx mouse model of Duchenne muscular dystrophy. This study provides new insights into the therapeutic utility of targeting defects in NO-cGMP signalling with PDE5 inhibitors in dystrophin-deficient muscle.

Project description:Dystrophinopathies cover a spectrum of rare progressive X-linked muscle diseases, arising from DMD mutations. They are among the most common pediatric muscular dystrophies, being Duchenne muscular dystrophy (DMD) the most severe form. Despite the fact that there is still no cure for these serious diseases, unprecedented advances are being made for the development of therapies for DMD. Some of which are already conditionally approved: exon skipping and premature stop codon read-through. The present work aimed to characterize the mutational spectrum of DMD in an Argentinian cohort, to identify candidates for available pharmacogenetic treatments and finally, to conduct a comparative analysis of the Latin American (LA) frequencies of mutations amenable for available DMD therapies. We studied 400 patients with clinical diagnosis of dystrophinopathy, implementing a diagnostic molecular algorithm including: MLPA/PCR/Sanger/Exome and bioinformatics. We also performed a meta-analysis of LA's metrics for DMD available therapies. The employed algorithm resulted effective for the achievement of differential diagnosis, reaching a detection rate of 97%. Because of this, corticosteroid treatment was correctly indicated and validated in 371 patients with genetic confirmation of dystrophinopathy. Also, 20 were eligible for exon skipping of exon 51, 21 for exon 53, 12 for exon 45 and another 70 for premature stop codon read-through therapy. We determined that 87.5% of DMD patients will restore the reading frame with the skipping of only one exon. Regarding nonsense variants, UGA turned out to be the most frequent premature stop codon observed (47%). According to the meta-analysis, only four LA countries (Argentina, Brazil, Colombia and Mexico) provide the complete molecular algorithm for dystrophinopathies. We observed different relations among the available targets for exon skipping in the analyzed populations, but a more even proportion of nonsense variants (∼40%). In conclusion, this manuscript describes the theragnosis carried out in Argentinian dystrophinopathy patients. The implemented molecular algorithm proved to be efficient for the achievement of differential diagnosis, which plays a crucial role in patient management, determination of the standard of care and genetic counseling. Finally, this work contributes with the international efforts to characterize the frequencies and variants in LA, pillars of drug development and theragnosis.

Dataset Information

Don't forget the trunk in Duchenne muscular dystrophy patients: more muscle weakness and compensation than expected.

Publications

Don't forget the trunk in Duchenne muscular dystrophy patients: more muscle weakness and compensation than expected.

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