scholarly journals Startle responses in Duchenne muscular dystrophy: a novel biomarker of brain dystrophin deficiency

2021 ◽  
Author(s):  
Kate Maresh ◽  
Andriani Papageorgiou ◽  
Deborah Ridout ◽  
Neil A. Harrison ◽  
William Mandy ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Objective Measure ◽  
Mean Difference ◽  
Extinction Phase ◽  
Variable Degree ◽  
Neuropsychological Measures ◽  
Increased Risk ◽  
Dystrophin Deficiency ◽  
Conditioned Responses

AbstractDuchenne muscular dystrophy (DMD) is characterised by loss of dystrophin in muscle. Patients affected by DMD also have variable degree of intellectual disability and neurobehavioural co-morbidities. In contrast to muscle, in which a single full-length isoform (Dp427) is produced, multiple dystrophin isoforms are produced in the brain, and their deficiency accounts for the variability of CNS manifestations, with increased risk of comorbidities in patients carrying mutations affecting the 3’ end of gene, disrupting the shorter Dp140 and Dp71 isoforms. The mdx mouse model of DMD lacks Dp427 in muscle and CNS and exhibits exaggerated startle responses to threat, linked to the deficiency of dystrophin in limbic structures such as the amygdala, which normalise with postnatal brain dystrophin-restoration therapies. A pathological startle response is not a recognised feature of DMD, and its characterisation has implications for improved clinical management and translational research.To investigate startle responses in DMD, we used a novel fear-conditioning task in an observational study of 56 males aged 7-12 years (31 DMD, mean age 9.7±1.8 years; 25 Controls, mean age 9.6±1.4 years). Trials of two neutral visual stimuli were presented to participants: one ‘safe’ cue presented alone; one ‘threat’ cue paired with an aversive noise to enable conditioning of physiological startle responses (skin conductance response, SCR; heart rate, HR). Retention of conditioned physiological responses was subsequently tested with presentation of both cues without the aversive noise in an ‘extinction’ phase. Primary outcomes were the magnitude of the initial unconditioned SCR and HR change responses to the aversive ‘threat’ and acquisition and retention of conditioned responses after conditioning. Secondary outcomes were neuropsychological measures and genotype associations.The initial (unconditioned) mean SCR to threat was greater in DMD than Controls (Mean difference 3.0 µS (95% CI 1.0, 5.1), P=.004), associated with a significant threat-induced bradycardia only in the DMD group (mean difference -5.6 bpm (95% CI 0.51, 16.9); P=.04). DMD participants found the task more aversive than Controls, consequently early termination during the extinction phase occurred in 26% of the DMD group (vs. 0% Controls; P=.007).This study provides the first evidence that boys with DMD show increased unconditioned startle responses to threat, similar to the mdx mouse phenotype that also responds to brain dystrophin restoration. Our study provides new insights into the neurobiology underlying the complex neuropsychiatric co-morbidities in DMD and defines an objective measure of this CNS phenotype, which will be valuable for future CNS-targeted dystrophin-restoration studies.

scholarly journals Autophagy in the heart is enhanced and independent of disease progression in mus musculus dystrophinopathy models

2019 ◽  
Vol 8 ◽  
pp. 204800401987958
Author(s):  
HR Spaulding ◽  
C Ballmann ◽  
JC Quindry ◽  
MB Hudson ◽  
JT Selsby
Keyword(s):  
Skeletal Muscle ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Disease Progression ◽  
Gene Mutations ◽  
Dystrophin Gene ◽  
Mdx Mice ◽  
Dystrophin Deficiency ◽  
Muscle Wasting Disease ◽  
Dystrophin Protein

Background Duchenne muscular dystrophy is a muscle wasting disease caused by dystrophin gene mutations resulting in dysfunctional dystrophin protein. Autophagy, a proteolytic process, is impaired in dystrophic skeletal muscle though little is known about the effect of dystrophin deficiency on autophagy in cardiac muscle. We hypothesized that with disease progression autophagy would become increasingly dysfunctional based upon indirect autophagic markers. Methods Markers of autophagy were measured by western blot in 7-week-old and 17-month-old control (C57) and dystrophic (mdx) hearts. Results Counter to our hypothesis, markers of autophagy were similar between groups. Given these surprising results, two independent experiments were conducted using 14-month-old mdx mice or 10-month-old mdx/Utrn± mice, a more severe model of Duchenne muscular dystrophy. Data from these animals suggest increased autophagosome degradation. Conclusion Together these data suggest that autophagy is not impaired in the dystrophic myocardium as it is in dystrophic skeletal muscle and that disease progression and related injury is independent of autophagic dysfunction.

Vitamin D in the prevention and treatment of comorbid conditions in Duchenne muscular dystrophy

2021 ◽  
Vol 2 (1) ◽  
pp. 38-50
Author(s):  
Tatiana A. Gremiakova ◽  
Vasiliy M. Souslov ◽  
Gulzhan E. Sakbaeva ◽  
Andrey A. Stepanov
Keyword(s):  
Vitamin D ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Steroid Therapy ◽  
Motor Development ◽  
Smooth Muscles ◽  
Comorbid Conditions ◽  
Increased Risk ◽  
Positive Effect ◽  
Tubular Bones

Duchenne muscular dystrophy (DMD) is an X-linked recessive degenerative neuromuscular disorder due to a deficiency of dystrophin protein. This protein is most common in skeletal and cardiac muscles, to a lesser extent in smooth muscles and the brain. With DMD, progressive damage and muscle degeneration, a delay in motor development, and respiratory cardiac disorders are progressing. Patients with DMD have an increased risk of developing osteoporosis, fractures of the tubular bones and vertebrae, and neurocognitive impairment. Vitamin D is recommended prophylactically for DMD since many studies have shown its deficiency. The purpose of this work is to consolidate the literature data on the vitamin D deficiency in DMD patients and its effects on the development of concurrent comorbid conditions of the musculoskeletal, endocrine, and nervous systems. The authors discuss data concerning the appropriate level of vitamin D throughout the life span of DMD has a positive effect on the course of the disease patients’ quality of life ends. Primary clinical outcomes of vitamin D normalization include prevention of the development of osteoporosis (especially after the start of steroid therapy), fractures of the tubular bones and vertebrae, prolonged ability to walk, more effective treatment with bisphosphonates, including a decrease in the number of complications during initial use and lower jaw necrosis, positive effect on the expression of autistic spectrum symptoms. For patients with long-term steroid therapy, metabolic and liver disorders, calcidiol could be used, allowing quick deficiency compensation instead of standard vitamin D preparations.

scholarly journals Dystrophin Deficiency Compromises Force Production of the Extensor Carpi Ulnaris Muscle in the Canine Model of Duchenne Muscular Dystrophy

PLoS ONE ◽  
2012 ◽  
Vol 7 (9) ◽  
pp. e44438 ◽  
Author(s):  
Hsiao T. Yang ◽  
Jin-Hong Shin ◽  
Chady H. Hakim ◽  
Xiufang Pan ◽  
Ronald L. Terjung ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Force Production ◽  
Canine Model ◽  
Extensor Carpi Ulnaris ◽  
Dystrophin Deficiency

Duchenne Muscular Dystrophy in a Girl Identified by Dystrophin Deficiency

1991 ◽  
Vol 22 (03) ◽  
pp. 163-165
Author(s):  
J. Maytal ◽  
A. Shanske ◽  
J. Fox ◽  
S. Lipper ◽  
L. Eviatar
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Dystrophin Deficiency

scholarly journals Biomarker-focused multi-drug combination therapy and repurposing trial in mdx mice

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0246507
Author(s):  
Michael Ziemba ◽  
Molly Barkhouse ◽  
Kitipong Uaesoontrachoon ◽  
Mamta Giri ◽  
Yetrib Hathout ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Serum Proteins ◽  
Mdx Mice ◽  
Proteomic Profiling ◽  
Treatment Groups ◽  
Dystrophin Deficiency ◽  
Repurposed Drugs ◽  
Good Concordance ◽  
Pharmacodynamic Biomarkers

Duchenne muscular dystrophy is initiated by dystrophin deficiency, but downstream pathophysiological pathways such as membrane instability, NFĸB activation, mitochondrial dysfunction, and induction of TGFβ fibrosis pathways are thought to drive the disability. Dystrophin replacement strategies are hopeful for addressing upstream dystrophin deficiency; however, all methods to date use semi-functional dystrophin proteins that are likely to trigger downstream pathways. Thus, combination therapies that can target multiple downstream pathways are important in treating DMD, even for dystrophin-replacement strategies. We sought to define blood pharmacodynamic biomarkers of drug response in the mdx mouse model of Duchenne muscular dystrophy using a series of repurposed drugs. Four-week-old mdx mice were treated for four weeks with four different drugs singly and in combination: vehicle, prednisolone, vamorolone, rituximab, β-aminoisobutyric acid (BAIBA) (11 treatment groups; n = 6/group). Blood was collected via cardiac puncture at study termination, and proteomic profiling was carried out using SOMAscan aptamer panels (1,310 proteins assayed). Prednisolone was tested alone and in combination with other drugs. It was found to have a good concordance of prednisolone-responsive biomarkers (56 increased by prednisolone, 39 decreased) focused on NFκB and TGFβ cascades. Vamorolone shared 45 (80%) of increased biomarkers and 13 (33%) of decreased biomarkers with prednisolone. Comparison of published human corticosteroid-responsive biomarkers to our mdx data showed 14% (3/22) concordance between mouse and human. Rituximab showed fewer drug-associated biomarkers, with the most significant being human IgG. On the other hand, BAIBA treatment (high and low dose) showed a drug-associated increase in 40 serum proteins and decreased 5 serum proteins. Our results suggest that a biomarker approach could be employed for assessing drug combinations in both mouse and human studies.

scholarly journals Orai1–STIM1 Regulates Increased Ca2+ Mobilization, Leading to Contractile Duchenne Muscular Dystrophy Phenotypes in Patient-Derived Induced Pluripotent Stem Cells

Biomedicines ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1589
Author(s):  
Tomoya Uchimura ◽  
Hidetoshi Sakurai
Keyword(s):  
Stem Cells ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Molecular Targets ◽  
Dystrophin Deficiency ◽  
Induced Pluripotent ◽  
Contractile Performance

Ca2+ overload is one of the factors leading to Duchenne muscular dystrophy (DMD) pathogenesis. However, the molecular targets of dystrophin deficiency-dependent Ca2+ overload and the correlation between Ca2+ overload and contractile DMD phenotypes in in vitro human models remain largely elusive. In this study, we utilized DMD patient-derived induced pluripotent stem cells (iPSCs) to differentiate myotubes using doxycycline-inducible MyoD overexpression, and searched for a target molecule that mediates dystrophin deficiency-dependent Ca2+ overload using commercially available chemicals and siRNAs. We found that several store-operated Ca2+ channel (SOC) inhibitors effectively prevented Ca2+ overload and identified that STIM1–Orai1 is a molecular target of SOCs. These findings were further confirmed by demonstrating that STIM1–Orai1 inhibitors, CM4620, AnCoA4, and GSK797A, prevented Ca2+ overload in dystrophic myotubes. Finally, we evaluated CM4620, AnCoA4, and GSK7975A activities using a previously reported model recapitulating a muscle fatigue-like decline in contractile performance in DMD. All three chemicals ameliorated the decline in contractile performance, indicating that modulating STIM1–Orai1-mediated Ca2+ overload is effective in rescuing contractile phenotypes. In conclusion, SOCs are major contributors to dystrophin deficiency-dependent Ca2+ overload through STIM1–Orai1 as molecular mediators. Modulating STIM1–Orai1 activity was effective in ameliorating the decline in contractile performance in DMD.

scholarly journals Teaching an Old Molecule New Tricks: Drug Repositioning for Duchenne Muscular Dystrophy

2019 ◽  
Vol 20 (23) ◽  
pp. 6053 ◽  
Author(s):  
Vitiello ◽  
Tibaudo ◽  
Pegoraro ◽  
Bello ◽  
Canton
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
State Of The Art ◽  
Drug Repositioning ◽  
Drug Repurposing ◽  
Biological Molecules ◽  
New Drugs ◽  
Dystrophin Deficiency ◽  
Pass Through ◽  
Pathogenic Effects

: Duchenne muscular dystrophy (DMD) is one of the most severe forms of inherited muscular dystrophies. The disease is caused by the lack of dystrophin, a structurally essential protein; hence, a definitive cure would necessarily have to pass through some form of gene and/or cell therapy. Cell- and genetic-based therapeutics for DMD have been explored since the 1990s and recently, two of the latter have been approved for clinical use, but their efficacy is still very low. In parallel, there have been great ongoing efforts aimed at targeting the downstream pathogenic effects of dystrophin deficiency using classical pharmacological approaches, with synthetic or biological molecules. However, as it is always the case with rare diseases, R&D costs for new drugs can represent a major hurdle for researchers and patients alike. This problem can be greatly alleviated by experimenting the use of molecules that had originally been developed for different conditions, a process known as drug repurposing or drug repositioning. In this review, we will describe the state of the art of such an approach for DMD, both in the context of clinical trials and pre-clinical studies.

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