scholarly journals Transplacental injection of somite-derived cells in mdx mouse embryos for the correction of dystrophin deficiency

2000 ◽  
Vol 9 (12) ◽  
pp. 1843-1852 ◽  
Author(s):  
Y. Torrente
Keyword(s):  
Mouse Embryos ◽  
Mdx Mouse ◽  
Dystrophin Deficiency

scholarly journals Normal myogenic cells from newborn mice restore normal histology to degenerating muscles of the mdx mouse.

1990 ◽  
Vol 111 (6) ◽  
pp. 2437-2449 ◽  
Author(s):  
J E Morgan ◽  
E P Hoffman ◽  
T A Partridge
Keyword(s):  
Skeletal Muscle ◽  
Muscle Fibers ◽  
Mdx Mouse ◽  
Newborn Mouse ◽  
Normal Muscle ◽  
Newborn Mice ◽  
X Ray ◽  
Dystrophin Deficiency ◽  
Regenerated Fibers ◽  
Muscle Precursor Cells

Dystrophin deficiency in skeletal muscle of the x-linked dystrophic (mdx) mouse can be partially remedied by implantation of normal muscle precursor cells (mpc) (Partridge, T. A., J. E. Morgan, G. R. Coulton, E. P. Hoffman, and L. M. Kunkel. 1989. Nature (Lond.). 337:176-179). However, it is difficult to determine whether this biochemical "rescue" results in any improvement in the structure or function of the treated muscle, because the vigorous regeneration of mdx muscle more than compensates for the degeneration (Coulton, G. R., N. A. Curtin, J. E. Morgan, and T. A. Partridge. 1988. Neuropathol. Appl. Neurobiol. 14:299-314). By using x-ray irradiation to prevent mpc proliferation, it is possible to study loss of mdx muscle fibers without the complicating effect of simultaneous fiber regeneration. Thus, improvements in fiber survival resulting from any potential therapy can be detected easily (Wakeford, S., D. J. Watt, and T. A. Patridge. 1990. Muscle & Nerve.) Here, we have implanted normal mpc, obtained from newborn mice, into such preirradiated mdx muscles, finding that it is far more extensively permeated and replaced by implanted mpc than is nonirradiated mdx muscle; this is evident both from analysis of glucose-6-phosphate isomerase isoenzyme markers and from immunoblots and immunostaining of dystrophin in the treated muscles. Incorporation of normal mpc markedly reduces the loss of muscle fibers and the deterioration of muscle structure which otherwise occurs in irradiated mdx muscles. Surprisingly, the regenerated fibers are largely peripherally nucleated, whereas regenerated mouse skeletal muscle fibers are normally centrally nucleated. We attribute this regeneration of apparently normal muscle to the tendency of newborn mouse mpc to recapitulate their neonatal ontogeny, even when grafted into 3-wk-old degenerating muscle.

Depolarization-induced contraction and SR function in mechanically skinned muscle fibers from dystrophic mdx mice

2003 ◽  
Vol 285 (3) ◽  
pp. C522-C528 ◽  
Author(s):  
David R. Plant ◽  
Gordon S. Lynch
Keyword(s):  
Muscle Fibers ◽  
Voltage Regulation ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
Channel Activity ◽  
Release Channel ◽  
Transverse Tubular System ◽  
Skinned Muscle ◽  
Dystrophin Deficiency ◽  
And Control

Dystrophin is absent in muscle fibers of patients with Duchenne muscular dystrophy (DMD) and in muscle fibers from the mdx mouse, an animal model of DMD. Disrupted excitation-contraction (E-C) coupling has been postulated to be a functional consequence of the lack of dystrophin, although the evidence for this is not entirely clear. We used mechanically skinned fibers (with a sealed transverse tubular system) prepared from fast extensor digitorum longus muscles of wild-type control and dystrophic mdx mice to test the hypothesis that dystrophin deficiency would affect the depolarization-induced contractile response (DICR) and sarcoplasmic reticulum (SR) function. DICR was similar in muscle fibers from mdx and control mice, indicating normal voltage regulation of Ca2+ release. Nevertheless, rundown of DICR (<50% of initial) was reached more rapidly in fibers from mdx than control mice [control: 32 ± 5 depolarizations ( n = 14 fibers) vs. mdx: 18 ± 1 depolarizations ( n = 7) before rundown, P < 0.05]. The repriming rate for DICRs was decreased in fibers from mdx mice, with lower submaximal DICR observed after 5, 10, and 20 s of repriming compared with fibers from control mice ( P < 0.05). SR Ca2+ reloading was not different in fibers from control and mdx mice, and no difference was observed in SR Ca2+ leak. Caffeine (2–7 mM)-induced contraction was diminished in fibers from mdx mice compared with control ( P < 0.05), indicating depressed SR Ca2+ release channel activity. Our findings indicate that fast fibers from mdx mice exhibit some impairment in the events mediating E-C coupling and SR Ca2+ release channel activity.

scholarly journals Genetic correction of dystrophin deficiency and skeletal muscle remodeling in adult MDX mouse via transplantation of retroviral producer cells.

1997 ◽  
Vol 100 (3) ◽  
pp. 620-628 ◽  
Author(s):  
A Fassati ◽  
D J Wells ◽  
P A Sgro Serpente ◽  
F S Walsh ◽  
S C Brown ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mdx Mouse ◽  
Dystrophin Deficiency ◽  
Muscle Remodeling

Contractile properties of diaphragm muscle segments from old mdx and old transgenic mdx mice

1997 ◽  
Vol 272 (6) ◽  
pp. C2063-C2068 ◽  
Author(s):  
G. S. Lynch ◽  
J. A. Rafael ◽  
R. T. Hinkle ◽  
N. M. Cole ◽  
J. S. Chamberlain ◽  
...  
Keyword(s):  
Life Span ◽  
Functional Properties ◽  
Transgenic Animal ◽  
Mouse Embryos ◽  
Diaphragm Muscle ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
Dystrophin Expression ◽  
Structural And Functional Properties

Diaphragm muscles of young (4- to 6-mo-old) mdx mice show severe fiber necrosis and have normalized forces and powers 60 and 46% of the values for control C57BL/10 mice. In contrast, microinjection of mdx mouse embryos with a truncated dystrophin minigene has produced young transgenic mdx (tg-mdx) mice with a level of dystrophin expression and structural and functional properties of diaphragm muscle strips measured in vitro not different from those of control mice. Whether dystrophin expression and functional corrections persist for the life span of these animals is not know. We tested the null hypothesis that, in old (24 mo) tg-mdx mice, dystrophin expression is adequate and diaphragm muscle strips have forces and powers not different from values for diaphragm muscle strips from young tg-mdx mice or control mice. Compared with control values, diaphragm muscle strips from old mdx mice had normalized forces and powers of 48 and 31%, respectively. Expression of dystrophin persisted in diaphragm muscles of old tg-mdx mice, and functional properties were not different from diaphragm muscles of young tg-mdx or young or old control mice. These results suggest that, with a transgenic animal approach, dystrophin expression and functional corrections persist for the life span of the animals.

scholarly journals Metabolic Alterations in Cardiomyocytes of Patients with Duchenne and Becker Muscular Dystrophies

2019 ◽  
Vol 8 (12) ◽  
pp. 2151 ◽  
Author(s):  
Gabriella Esposito ◽  
Antonella Carsana
Keyword(s):  
No Synthase ◽  
Muscular Dystrophies ◽  
Mdx Mouse ◽  
Oxygen Species ◽  
Metabolic Alterations ◽  
Pathophysiological Role ◽  
Dystrophin Deficiency ◽  
Cardiac Muscles ◽  
Species Production ◽  
Progressive Weakness

Duchenne and Becker muscular dystrophies (DMD/BMD) result in progressive weakness of skeletal and cardiac muscles due to the deficiency of functional dystrophin. Respiratory failure is a leading cause of mortality in DMD patients; however, improved management of the respiratory symptoms have increased patients’ life expectancy, thereby also increasing the clinical relevance of heart disease. In fact, the prevalence of cardiomyopathy, which significantly contributes to mortality in DMD patients, increases with age and disease progression, so that over 95% of adult patients has cardiomyopathy signs. We here review the current literature featuring the metabolic alterations observed in the dystrophic heart of the mdx mouse, i.e., the best-studied animal model of the disease, and discuss their pathophysiological role in the DMD heart. It is well assessed that dystrophin deficiency is associated with pathological alterations of lipid metabolism, intracellular calcium levels, neuronal nitric oxide (NO) synthase localization, and NO and reactive oxygen species production. These metabolic stressors contribute to impair the function of the cardiac mitochondrial bulk, which has a relevant pathophysiological role in the development of cardiomyopathy. In fact, mitochondrial dysfunction becomes more severe as the dystrophic process progresses, thereby indicating it may be both the cause and the consequence of the dystrophic process in the DMD heart.

Fasting Increases the Extent of Muscle Necrosis in the mdx Mouse

1996 ◽  
Vol 90 (6) ◽  
pp. 467-472 ◽  
Author(s):  
T. R. Helliwell ◽  
P. A. MacLennan ◽  
A. McArdle ◽  
R. H. T. Edwards ◽  
M. J. Jackson
Keyword(s):  
Mdx Mouse ◽  
Mdx Mice ◽  
Energy Status ◽  
Wild Type ◽  
Muscle Fibre Size ◽  
Fed State ◽  
Fibre Size ◽  
High Prevalence ◽  
Dystrophin Deficiency ◽  
Muscle Necrosis

1. The effects of fasting for 48 h were investigated in CS7BL/10 (wild type) and age-matched C57BL/10 dystrophin-deficient (mdx) mice. 2. Fasting resulted in an increased percentage of necrotic fibres in muscles from the hindlimb and lumbar regions of mdx mice. The percentage of necrotic fibres of forelimb and chest muscles of mdx mice was unaltered by fasting. In wild-type mice, very few necrotic fibres were observed after fasting. 3. The necrotic changes in fasted mdx muscle were not accompanied by altered energy status as evaluated by muscle ATP and phosphocreatine concentrations. 4. A significantly decreased rectal temperature was observed in mdx but not in wild-type mice after fasting. 5. Fasting would normally be expected to cause a reduction in muscle fibre size. The high prevalence of necrosis in fasted mdx mice is therefore an unusual response that may be related to disturbance of the mechanisms which, in the fed state, compensate for the dystrophin deficiency in these animals.

scholarly journals Cardiac Protection after Systemic Transplant of Dystrophin Expressing Chimeric (DEC) Cells to the mdx Mouse Model of Duchenne Muscular Dystrophy

2019 ◽  
Vol 15 (6) ◽  
pp. 827-841 ◽  
Author(s):  
Maria Siemionow ◽  
M. Malik ◽  
P. Langa ◽  
J. Cwykiel ◽  
S. Brodowska ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Cardiac Function ◽  
Premature Death ◽  
Dystrophin Gene ◽  
Mdx Mouse ◽  
Cardiac Protection ◽  
Intraosseous Injection ◽  
Dystrophin Deficiency ◽  
Cardiac Muscles

Abstract Duchenne Muscular Dystrophy (DMD) is a progressive lethal disease caused by X-linked mutations of the dystrophin gene. Dystrophin deficiency clinically manifests as skeletal and cardiac muscle weakness, leading to muscle wasting and premature death due to cardiac and respiratory failure. Currently, no cure exists. Since heart disease is becoming a leading cause of death in DMD patients, there is an urgent need to develop new more effective therapeutic strategies for protection and improvement of cardiac function. We previously reported functional improvements correlating with dystrophin restoration following transplantation of Dystrophin Expressing Chimeric Cells (DEC) of myoblast origin in the mdx and mdx/scid mouse models. Here, we confirm positive effect of DEC of myoblast (MBwt/MBmdx) and mesenchymal stem cells (MBwt/MSCmdx) origin on protection of cardiac function after systemic DEC transplant. Therapeutic effect of DEC transplant (0.5 × 106) was assessed by echocardiography at 30 and 90 days after systemic-intraosseous injection to the mdx mice. At 90 days post-transplant, dystrophin expression in cardiac muscles of DEC injected mice significantly increased (15.73% ± 5.70 –MBwt/MBmdx and 5.22% ± 1.10 – MBwt/MSCmdx DEC) when compared to vehicle injected controls (2.01% ± 1.36) and, correlated with improved ejection fraction and fractional shortening on echocardiography. DEC lines of MB and MSC origin introduce a new promising approach based on the combined effects of normal myoblasts with dystrophin delivery capacities and MSC with immunomodulatory properties. Our study confirms feasibility and efficacy of DEC therapy on cardiac function and represents a novel therapeutic strategy for cardiac protection and muscle regeneration in DMD.

scholarly journals Cognitive dysfunction in Duchenne muscular dystrophy: a possible role for neuromodulatory immune molecules

2016 ◽  
Vol 116 (3) ◽  
pp. 1304-1315 ◽  
Author(s):  
Mark G. Rae ◽  
Dervla O'Malley
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Learning And Memory ◽  
Cognitive Dysfunction ◽  
Hippocampal Neurons ◽  
Premature Death ◽  
Brain Regions ◽  
Mdx Mouse ◽  
Structural Protein ◽  
Dystrophin Deficiency

Duchenne muscular dystrophy (DMD) is an X chromosome-linked disease characterized by progressive physical disability, immobility, and premature death in affected boys. Underlying the devastating symptoms of DMD is the loss of dystrophin, a structural protein that connects the extracellular matrix to the cell cytoskeleton and provides protection against contraction-induced damage in muscle cells, leading to chronic peripheral inflammation. However, dystrophin is also expressed in neurons within specific brain regions, including the hippocampus, a structure associated with learning and memory formation. Linked to this, a subset of boys with DMD exhibit nonprogressing cognitive dysfunction, with deficits in verbal, short-term, and working memory. Furthermore, in the genetically comparable dystrophin-deficient mdx mouse model of DMD, some, but not all, types of learning and memory are deficient, and specific deficits in synaptogenesis and channel clustering at synapses has been noted. Little consideration has been devoted to the cognitive deficits associated with DMD compared with the research conducted into the peripheral effects of dystrophin deficiency. Therefore, this review focuses on what is known about the role of full-length dystrophin (Dp427) in hippocampal neurons. The importance of dystrophin in learning and memory is assessed, and the potential importance that inflammatory mediators, which are chronically elevated in dystrophinopathies, may have on hippocampal function is also evaluated.

Acute pathophysiological effects of muscle-expressed Dp71 transgene on normal and dystrophic mouse muscle

2003 ◽  
Vol 95 (5) ◽  
pp. 1861-1866 ◽  
Author(s):  
Sascha Wieneke ◽  
Peter Heimann ◽  
Sigalit Leibovitz ◽  
Uri Nudel ◽  
Harald Jockusch
Keyword(s):  
Muscular Dystrophy ◽  
Dystrophin Gene ◽  
Force Generation ◽  
Mdx Mouse ◽  
Mouse Muscle ◽  
Tetanic Force ◽  
Dystrophin Deficiency ◽  
Associated Proteins ◽  
Isometric Twitch ◽  
Tetanic Tension

products of the dystrophin gene range from the 427-kDa full-length dystrophin to the 70.8-kDa Dp71. Dp427 is expressed in skeletal muscle, where it links the actin cytoskeleton with the extracellular matrix via a complex of dystrophin-associated proteins (DAPs). Dystrophin deficiency disrupts the DAP complex and causes muscular dystrophy in humans and the mdx mouse. Dp71, the major nonmuscle product, consists of the COOH-terminal part of dystrophin, including the binding site for the DAP complex but lacks binding sites for microfilaments. Dp71 transgene (Dp71tg) expressed in mdx muscle restores the DAP complex but does not prevent muscle degeneration. In wild-type (WT) mouse muscle, Dp71tg causes a mild muscular dystrophy. In this study, we tested, using isolated extensor digitorum longus muscles, whether Dp71tg exerts acute influences on force generation and sarcolemmal stress resistance. In WT muscles, there was no effect on isometric twitch and tetanic force generation, but with a cytomegalovirus promotor-driven transgene, contraction with stretch led to sarcolemmal ruptures and irreversible loss of tension. In MDX muscle, Dp71tg reduced twitch and tetanic tension but did not aggravate sarcolemmal fragility. The adverse effects of Dp71 in muscle are probably due to its competition with dystrophin and utrophin (in MDX muscle) for binding to the DAP complex.

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