scholarly journals Absence of extraocular muscle pathology in Duchenne's muscular dystrophy: role for calcium homeostasis in extraocular muscle sparing.

1995 ◽  
Vol 182 (2) ◽  
pp. 467-475 ◽  
Author(s):  
T S Khurana ◽  
R A Prendergast ◽  
H S Alameddine ◽  
F M Tomé ◽  
M Fardeau ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Calcium Homeostasis ◽  
Extraocular Muscle ◽  
Striated Muscle ◽  
Extraocular Muscles ◽  
Muscle Pathology ◽  
Dystrophin Deficiency ◽  
Muscle Groups ◽  
Duchenne's Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is characterized by clinical weakness and progressive necrosis of striated muscle as a consequence of dystrophin deficiency. While all skeletal muscle groups are thought to be affected, enigmatically, the extraocular muscles (EOM) appear clinically unaffected. Here we show that dystrophin deficiency does not result in myonecrosis or pathologically elevated levels of intracellular calcium ([Ca2+]i) in EOM. At variance with a previous report, we find no evidence for dystrophin-related protein/utrophin up-regulation in EOM. In vitro experiments demonstrate that extraocular muscles are inherently more resistant to necrosis caused by pharmacologically elevated [Ca2+]i levels when compared with pectoral musculature. We believe that EOM are spared in DMD because of their intrinsic ability to maintain calcium homeostasis better than other striated muscle groups. Our results indicate that modulating levels of [Ca2+]i in muscle may be of potential therapeutic use in DMD.

Dynamic Gait Electromyography Study in Duchenne Muscular Dystrophy (DMD) Patients∗

Foot & Ankle ◽  
1980 ◽  
Vol 1 (2) ◽  
pp. 78-83 ◽  
Author(s):  
Gregory J. Melkonian ◽  
Robert L. Cristofaro ◽  
Jacquelin Perry ◽  
John D. Hsu
Keyword(s):  
Muscular Dystrophy ◽  
Phase Changes ◽  
Foot Deformities ◽  
Posterior Tibial Tendon ◽  
Interosseous Ligament ◽  
Posterior Tibial ◽  
Tendon Lengthening ◽  
Muscle Groups ◽  
Duchenne's Muscular Dystrophy ◽  
Dynamic Gait

Preoperative and postoperative dynamic gait electromyography (EMG) was performed on 15 patients 8 to 13 years of age with Duchenne's muscular dystrophy who underwent Achilles tendon lengthening and posterior tibial tendon transfer anteriorly through the interosseous ligament for correction of equinus and equinovarus foot deformities. The muscles tested preoperatively (anterior tibial, soleus, gastrocnemius, posterior tibial, peroneal longus, and peroneal brevis) showed phase changes. It is believed that patients with weakened leg muscles fire multiple muscle groups out of phase in an attempt to overcome the action of the stronger muscles, thus stabilizing the limb for ambulation. Postoperative EMGs, performed with the patients walking in long leg braces after the deformity had been corrected, showed litte activity in the muscles tested. As the patients became dependent on the brace, the need for the muscles to be active out of phase was eliminated. The transferred posterior tibial muscle appeared to be active both clinically and electromyographically.

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 The root cause of Duchenne muscular dystrophy is the lack of dystrophin in smooth muscle of blood vessels rather than in skeletal muscle per se

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 1321
Author(s):  
Nadesan Gajendran
Keyword(s):  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Smooth Muscle ◽  
Muscular Dystrophy ◽  
Blood Vessels ◽  
No Production ◽  
Knock Out ◽  
Dystrophin Expression ◽  
Dystrophin Deficiency

Background: The dystrophin protein is part of the dystrophin associated protein complex (DAPC) linking the intracellular actin cytoskeleton to the extracellular matrix. Mutations in the dystrophin gene cause Duchenne and Becker muscular dystrophy (D/BMD). Neuronal nitric oxide synthase associates with dystrophin in the DAPC to generate the vasodilator nitric oxide (NO). Systemic dystrophin deficiency, such as in D/BMD, results in muscle ischemia, injury and fatigue during exercise as dystrophin is lacking, affecting NO production and hence vasodilation. The role of neuregulin 1 (NRG) signaling through the epidermal growth factor family of receptors ERBB2 and ERBB4 in skeletal muscle has been controversial, but it was shown to phosphorylate α-dystrobrevin 1 (α-DB1), a component of the DAPC. The aim of this investigation was to determine whether NRG signaling had a functional role in muscular dystrophy. Methods: Primary myoblasts (muscle cells) were isolated from conditional knock-out mice containing lox P flanked ERBB2 and ERBB4 receptors, immortalized and exposed to CRE recombinase to obtain Erbb2/4 double knock-out (dKO) myoblasts where NRG signaling would be eliminated. Myotubes, the in vitro equivalent of muscle fibers, formed by fusion of the lox P flanked Erbb2/4 myoblasts as well as the Erbb2/4 dKO myoblasts were then used to identify changes in dystrophin expression. Results: Elimination of NRG signaling resulted in the absence of dystrophin demonstrating that it is essential for dystrophin expression. However, unlike the DMD mouse model mdx, with systemic dystrophin deficiency, lack of dystrophin in skeletal muscles of Erbb2/4 dKO mice did not result in muscular dystrophy. In these mice, ERBB2/4, and thus dystrophin, is expressed in the smooth muscle of blood vessels allowing normal blood flow through vasodilation during exercise. Conclusions: Dystrophin deficiency in smooth muscle of blood vessels, rather than in skeletal muscle, is the main cause of disease progression in DMD.

scholarly journals Interleukins 4 and 13 Induce Exon Skipping of Mutant Dystrophin Pre-mRNA to Restore Dystrophin Production

2017 ◽  
Author(s):  
SiewHui Low ◽  
Chen-Ming Fan
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Exon Skipping ◽  
Interleukin 4 ◽  
Unexpected Finding ◽  
Systemic Delivery ◽  
Clinical Safety ◽  
Reading Frame ◽  
Muscle Groups

AbstractDuchenne muscular dystrophy is (DMD) a lethal muscle degenerative disease caused by nonsense or out of frame deletion mutations in the DMD gene1, which encodes Dystrophin2,3. While multiple therapeutic strategies to ameliorate the disease symptoms are under development, there is currently no cure. Here we report an unexpected finding that intramuscular injections of the anti-inflammatory interleukin 4 or 13 (IL4/13) not only reduce inflammation but also restore Dystrophin protein production in the mdx mouse model4. IL4/13 restores Dystrophin production by inducing changes in the Dmd pre-mRNA splicing pattern that exclude the mutated exon and restore the reading frame. We further show that systemic delivery of IL4-Fc can restore Dystrophin in multiple muscle groups and increase muscle endurance and strength in mdx mice. Importantly, IL4/13 treatment of mdx myoblasts is sufficient to induce exon skipping and restore Dmd reading frame in vitro. Moreover, IL4-treated DMD patient myoblasts produce Dystrophin-positive myofibers after transplantation. In light of the established clinical safety of IL4 treatment5,6, we recommend IL4 as an agent of immediate consideration for treating Duchenne muscular dystrophy.

The sparing of extraocular muscle in dystrophinopathy is lost in mice lacking utrophin and dystrophin

1998 ◽  
Vol 111 (13) ◽  
pp. 1801-1811 ◽  
Author(s):  
J.D. Porter ◽  
J.A. Rafael ◽  
R.J. Ragusa ◽  
J.K. Brueckner ◽  
J.I. Trickett ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Extraocular Muscle ◽  
Skeletal Muscles ◽  
Extraocular Muscles ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
Fiber Types ◽  
Eye Muscle ◽  
Muscle Sparing

The extraocular muscles are one of few skeletal muscles that are structurally and functionally intact in Duchenne muscular dystrophy. Little is known about the mechanisms responsible for differential sparing or targeting of muscle groups in neuromuscular disease. One hypothesis is that constitutive or adaptive properties of the unique extraocular muscle phenotype may underlie their protection in dystrophinopathy. We assessed the status of extraocular muscles in the mdx mouse model of muscular dystrophy. Mice showed mild pathology in accessory extraocular muscles, but no signs of pathology were evident in the principal extraocular muscles at any age. By immunoblotting, the extraocular muscles of mdx mice exhibited increased levels of a dystrophin analog, dystrophin-related protein or utrophin. These data suggest, but do not provide mechanistic evidence, that utrophin mediates eye muscle protection. To examine a potential causal relationship, knockout mouse models were used to determine whether eye muscle sparing could be reversed. Mice lacking expression of utrophin alone, like the dystrophin-deficient mdx mouse, showed no pathological alterations in extraocular muscle. However, mice deficient in both utrophin and dystrophin exhibited severe changes in both the accessory and principal extraocular muscles, with the eye muscles affected more adversely than other skeletal muscles. Selected extraocular muscle fiber types still remained spared, suggesting the operation of an alternative mechanism for muscle sparing in these fiber types. We propose that an endogenous upregulation of utrophin is mechanistic in protecting extraocular muscle in dystrophinopathy. Moreover, data lend support to the hypothesis that interventions designed to increase utrophin levels may ameliorate the pathology in other skeletal muscles in Duchenne muscular dystrophy.

Abnormal calcium homeostasis in Duchenne muscular dystrophy myotubes contracting in vitro

Cell Calcium ◽  
1995 ◽  
Vol 18 (3) ◽  
pp. 177-186 ◽  
Author(s):  
N. Imbert ◽  
C. Cognard ◽  
G. Duport ◽  
C. Guillou ◽  
G. Raymond
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Calcium Homeostasis

Verapamil and calcium-stimulated enzyme efflux from skeletal muscle.

1982 ◽  
Vol 28 (7) ◽  
pp. 1482-1484 ◽  
Author(s):  
R Anand ◽  
A E Emery
Keyword(s):  
Skeletal Muscle ◽  
Creatine Kinase ◽  
Lactate Dehydrogenase ◽  
Muscular Dystrophy ◽  
Human Skeletal Muscle ◽  
Biochemical Abnormality ◽  
Calcium Blocker ◽  
Normal Human ◽  
Duchenne's Muscular Dystrophy

Abstract An early and significant biochemical abnormality in Duchenne's muscular dystrophy is an increase in intracellular calcium. We have found that the "calcium-blocker" drug verapamil inhibits calcium-stimulated efflux of creatine kinase (EC 2.7.3.2) and lactate dehydrogenase (EC 1.1.1.27) in vitro from normal human skeletal muscle at therapeutic concentrations. Such a calcium blocker might therefore be useful in the treatment of Duchenne's muscular dystrophy.

scholarly journals The root cause of Duchenne muscular dystrophy is the lack of dystrophin in smooth muscle of blood vessels rather than in skeletal muscle per se

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 1321 ◽  
Author(s):  
Nadesan Gajendran
Keyword(s):  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Smooth Muscle ◽  
Muscular Dystrophy ◽  
Blood Vessels ◽  
No Production ◽  
Knock Out ◽  
Dystrophin Expression ◽  
Dystrophin Deficiency

Background: The dystrophin protein is part of the dystrophin associated protein complex (DAPC) linking the intracellular actin cytoskeleton to the extracellular matrix. Mutations in the dystrophin gene cause Duchenne and Becker muscular dystrophy (D/BMD). Neuronal nitric oxide synthase associates with dystrophin in the DAPC to generate the vasodilator nitric oxide (NO). Systemic dystrophin deficiency, such as in D/BMD, results in muscle ischemia, injury and fatigue during exercise as dystrophin is lacking, affecting NO production and hence vasodilation. The role of neuregulin 1 (NRG) signaling through the epidermal growth factor family of receptors ERBB2 and ERBB4 in skeletal muscle has been controversial, but it was shown to phosphorylate α-dystrobrevin 1 (α-DB1), a component of the DAPC. The aim of this investigation was to determine whether NRG signaling had a functional role in muscular dystrophy. Methods: Primary myoblasts (muscle cells) were isolated from conditional knock-out mice containing lox P flanked ERBB2 and ERBB4 receptors, immortalized and exposed to Cre recombinase to obtain Erbb2/4 double knock-out (dKO) myoblasts where NRG signaling would be eliminated. Myotubes, the in vitro equivalent of muscle fibers, formed by fusion of the lox P flanked Erbb2/4 myoblasts as well as the Erbb2/4 dKO myoblasts were then used to identify changes in dystrophin expression. Results: Elimination of NRG signaling resulted in the absence of dystrophin demonstrating that it is essential for dystrophin expression. However, unlike the DMD mouse model mdx, with systemic dystrophin deficiency, lack of dystrophin in skeletal muscles of Erbb2/4 dKO mice did not result in muscular dystrophy. In these mice, ERBB2/4, and thus dystrophin, is still expressed in the smooth muscle of blood vessels allowing normal blood flow through vasodilation during exercise. Conclusions: Dystrophin deficiency in smooth muscle of blood vessels, rather than in skeletal muscle, is the main cause of disease progression in DMD.

Electron Microscopy of Fibroblasts from Myotonic Muscular Dystrophy Patients

1981 ◽  
Vol 39 ◽  
pp. 498-499
Author(s):  
S. E. Miller ◽  
G. B. Hartwig ◽  
R. A. Nielsen ◽  
A. P. Frost ◽  
A. D. Roses
Keyword(s):  
Electron Microscopy ◽  
Muscular Dystrophy ◽  
Genetic Diseases ◽  
Skin Fibroblasts ◽  
Inborn Errors ◽  
Cytoplasmic Inclusions ◽  
Cultured Skin ◽  
Myotonic Muscular Dystrophy ◽  
Glycosaminoglycan Metabolism

Many genetic diseases can be demonstrated in skin cells cultured in vitro from patients with inborn errors of metabolism. Since myotonic muscular dystrophy (MMD) affects many organs other than muscle, it seems likely that this defect also might be expressed in fibroblasts. Detection of an alteration in cultured skin fibroblasts from patients would provide a valuable tool in the study of the disease as it would present a readily accessible and controllable system for examination. Furthermore, fibroblast expression would allow diagnosis of fetal and presumptomatic cases. An unusual staining pattern of MMD cultured skin fibroblasts as seen by light microscopy, namely, an increase in alcianophilia and metachromasia, has been reported; both these techniques suggest an altered glycosaminoglycan metabolism An altered growth pattern has also been described. One reference on cultured skin fibroblasts from a different dystrophy (Duchenne Muscular Dystrophy) reports increased cytoplasmic inclusions seen by electron microscopy. Also, ultrastructural alterations have been reported in muscle and thalamus biopsies from MMD patients, but no electron microscopical data is available on MMD cultured skin fibroblasts.

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