Severe muscle dysfunction precedes collagen tissue proliferation in mdx mouse diaphragm

2003 ◽  
Vol 94 (5) ◽  
pp. 1744-1750 ◽  
Author(s):  
Catherine Coirault ◽  
Bernadette Pignol ◽  
Racquel N. Cooper ◽  
Gillian Butler-Browne ◽  
Pierre-Etienne Chabrier ◽  
...  
Keyword(s):  
Muscle Performance ◽  
Diaphragm Muscle ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
Cycle Duration ◽  
Shortening Velocity ◽  
Tissue Proliferation ◽  
Mouse Diaphragm ◽  
Muscular Dysfunction ◽  
Time Cycle

After extensive necrosis, progressive diaphragm muscle weakness in the mdx mouse is thought to reflect progressive replacement of contractile tissue by fibrosis. However, little has been documented on diaphragm muscle performance at the stage at which necrosis and fibrosis are limited. Diaphragm morphometric characteristics, muscle performance, and cross-bridge (CB) properties were investigated in 6-wk-old control (C) and mdx mice. Compared with C, maximum tetanic tension and shortening velocity were 37 and 32% lower, respectively, in mdx mice (each P < 0.05). The total number of active CB per millimeter squared (13.0 ± 1.2 vs. 18.4 ± 1.7 × 109/mm2, P < 0.05) and the CB elementary force (8.0 ± 0.2 vs. 9.0 ± 0.1 pN, P < 0.01) were lower in mdx than in C. The time cycle duration was lower in mdx than in C (127 ± 18 vs. 267 ± 61 ms, P < 0.05). Percentages of fiber necrosis represented 2.8 ± 0.6% of the total muscle fibers, and collagen surface area occupied 3.6 ± 0.7% in mdx diaphragm. Our results pointed to severe muscular dysfunction in mdx mouse diaphragm, despite limited necrotic and fibrotic lesions.

scholarly journals N-acetylcysteine Decreases Fibrosis and Increases Force-Generating Capacity of mdx Diaphragm

Antioxidants ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 581 ◽  
Author(s):  
David P. Burns ◽  
Sarah E. Drummond ◽  
Dearbhla Bolger ◽  
Amélie Coiscaud ◽  
Kevin H. Murphy ◽  
...  
Keyword(s):  
Respiratory Muscle ◽  
Immune Cell ◽  
Muscle Performance ◽  
Diaphragm Muscle ◽  
Cell Infiltration ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
Immune Cell Infiltration ◽  
Wild Type ◽  
Generating Capacity

Respiratory muscle weakness occurs due to dystrophin deficiency in Duchenne muscular dystrophy (DMD). The mdx mouse model of DMD shows evidence of impaired respiratory muscle performance with attendant inflammation and oxidative stress. We examined the effects of N-acetylcysteine (NAC) supplementation on respiratory system performance in mdx mice. Eight-week-old male wild type (n = 10) and mdx (n = 20) mice were studied; a subset of mdx (n = 10) received 1% NAC in the drinking water for 14 days. We assessed breathing, diaphragm, and external intercostal electromyogram (EMG) activities and inspiratory pressure during ventilatory and non-ventilatory behaviours. Diaphragm muscle structure and function, cytokine concentrations, glutathione status, and mRNA expression were determined. Diaphragm force-generating capacity was impaired in mdx compared with wild type. Diaphragm muscle remodelling was observed in mdx, characterized by increased muscle fibrosis, immune cell infiltration, and central myonucleation. NAC supplementation rescued mdx diaphragm function. Collagen content and immune cell infiltration were decreased in mdx + NAC compared with mdx diaphragms. The cytokines IL-1β, IL-6 and KC/GRO were increased in mdx plasma and diaphragm compared with wild type; NAC decreased systemic IL-1β and KC/GRO concentrations in mdx mice. We reveal that NAC treatment improved mdx diaphragm force-generating capacity associated with beneficial anti-inflammatory and anti-fibrotic effects. These data support the potential use of NAC as an adjunctive therapy in human dystrophinopathies.

Global/temporal gene expression in diaphragm and hindlimb muscles of dystrophin-deficient (mdx) mice

2002 ◽  
Vol 283 (3) ◽  
pp. C773-C784 ◽  
Author(s):  
Karl Rouger ◽  
Martine Le Cunff ◽  
Marja Steenman ◽  
Marie-Claude Potier ◽  
Nathalie Gibelin ◽  
...  
Keyword(s):  
Dystrophin Gene ◽  
Diaphragm Muscle ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
First Year ◽  
Temporal Gene Expression ◽  
Cell Functions ◽  
Hindlimb Muscles ◽  
Genes Encoding ◽  
Dystrophin Protein

The mdx mouse is a model for human Duchenne muscular dystrophy (DMD), an X-linked degenerative disease of skeletal muscle tissue characterized by the absence of the dystrophin protein. The mdx mice display a much milder phenotype than DMD patients. After the first week of life when all mdx muscles evolve like muscles of young DMD patients, mdx hindlimb muscles substantially compensate for the lack of dystrophin, whereas mdx diaphragm muscle becomes progressively affected by the disease. We used cDNA microarrays to compare the expression profile of 1,082 genes, previously selected by a subtractive method, in control and mdx hindlimb and diaphragm muscles at 12 time points over the first year of the mouse life. We determined that 1) the dystrophin gene defect induced marked expression remodeling of 112 genes encoding proteins implicated in diverse muscle cell functions and 2) two-thirds of the observed transcriptomal anomalies differed between adult mdx hindlimb and diaphragm muscles. Our results showed that neither mdx diaphram muscle nor mdx hindlimb muscles evolve entirely like the human DMD muscles. This finding should be taken under consideration for the interpretation of future experiments using mdx mice as a model for therapeutic assays.

Inspiratory loading does not accelerate dystrophy inmdx mouse diaphragm: implications for regenerative therapy

2003 ◽  
Vol 94 (2) ◽  
pp. 411-419 ◽  
Author(s):  
Alexander S. Krupnick ◽  
Jianliang Zhu ◽  
Taitan Nguyen ◽  
Daniel Kreisel ◽  
Keki R. Balsara ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
Blue Dye ◽  
Regenerative Therapy ◽  
Regenerative Capacity ◽  
Progressive Degeneration ◽  
Mouse Diaphragm ◽  
The Relationship

Since the finding that the mdx mouse diaphragm, in contrast to limb muscles, undergoes progressive degeneration analogous to that seen in Duchenne muscular dystrophy, the relationship between the workload on a muscle and the pathogenesis of dystrophy has remained controversial. We increased the work performed by the mdx mouse diaphragm in vivo by tracheal banding and evaluated the progression of dystrophic changes in that muscle. Despite the establishment of dramatically increased respiratory workload and accelerated myofiber damage documented by Evans blue dye, no change in the pace of progression of dystrophy was seen in banded animals vs. unbanded, sham-operated controls. At the completion of the study, more centrally nucleated fibers were evident in the diaphragms of banded mdx mice than in sham-operated mdx controls, indicating that myofiber regeneration increases to meet the demands of the work-induced damage. These data suggest that there is untapped regenerative capacity in dystrophin-deficient muscle and validates experimental efforts aimed at augmenting regeneration within skeletal muscle as a therapeutic strategy in the treatment of dystrophinopathies.

Diaphragm tension reduced in dystrophic mice by an oxidant, hypochlorous acid

2010 ◽  
Vol 88 (2) ◽  
pp. 130-140
Author(s):  
Aude Lafoux ◽  
Alexandra Divet ◽  
Pascal Gervier ◽  
Corinne Huchet-Cadiou
Keyword(s):  
Skeletal Muscle ◽  
Sarcoplasmic Reticulum ◽  
Hypochlorous Acid ◽  
Muscle Cells ◽  
Skeletal Muscle Cells ◽  
Diaphragm Muscle ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
Skinned Fibres ◽  
Dystrophic Mice

In dystrophin-deficient skeletal muscle cells, in which Ca2+ homeostasis is disrupted and reactive oxygen species production is increased, we hypothesized that hypochlorous acid (HOCl), a strong H2O2-related free radical, damages contractile proteins and the sarcoplasmic reticulum. The aim of the present study was to investigate the effects of exposure to oxidative stress, generated by applying HOCl (100 µmol/L and 1 mmol/L), on the contractile function and sarcoplasmic reticulum properties of dystrophic mice. Experiments were performed on diaphragm muscle, which is severely affected in the mdx mouse, and the results were compared with those obtained in healthy (non-dystrophic) mice. In Triton-skinned fibres from C57BL/10 and mdx mice, 1 mmol/L HOCl increased myofibrillar Ca2+ sensitivity, but decreased maximal Ca2+-activated tension. In the presence of HOCl, higher concentrations of MgATP were required to produce rigor tensions. The interaction between HOCl and the Ca2+ uptake mechanisms was demonstrated using saponin-skinned fibres and sarcoplasmic reticulum vesicles. The results showed that HOCl, at micromolar or millimolar concentrations, can modify sarcoplasmic reticulum Ca2+ uptake and that this effect was more pronounced in diaphragm muscle from mdx mice. We conclude that in dystrophic diaphragm skeletal muscle cells, HOCl activates a cellular pathway that leads to an increase in the intracellular concentration of Ca2+.

scholarly journals The capacity of mdx mouse diaphragm muscle to do oscillatory work

2000 ◽  
Vol 522 (3) ◽  
pp. 457-466 ◽  
Author(s):  
E. Don Stevens ◽  
J. A. Faulkner
Keyword(s):  
Diaphragm Muscle ◽  
Mdx Mouse ◽  
Mouse Diaphragm

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 N‐Acetyl cysteine improves dystrophic ( mdx ) mouse diaphragm muscle quality and strength

2019 ◽  
Vol 33 (S1) ◽  
Author(s):  
David P Burns ◽  
Sarah E Drummond ◽  
Dearbhla Bolger ◽  
Kevin H Murphy ◽  
Amélie P Coiscaud ◽  
...  
Keyword(s):  
Muscle Quality ◽  
Diaphragm Muscle ◽  
Mdx Mouse ◽  
Mouse Diaphragm ◽  
Acetyl Cysteine

Stretch-activated calcium channel protein TRPC1 is correlated with the different degrees of the dystrophic phenotype in mdx mice

2011 ◽  
Vol 301 (6) ◽  
pp. C1344-C1350 ◽  
Author(s):  
Cíntia Yuri Matsumura ◽  
Ana Paula Tiemi Taniguti ◽  
Adriana Pertille ◽  
Humberto Santo Neto ◽  
Maria Julia Marques
Keyword(s):  
Calcium Channel ◽  
Transient Receptor Potential ◽  
Biceps Brachii ◽  
Receptor Potential ◽  
Diaphragm Muscle ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
Blue Dye ◽  
Channel Protein ◽  
Transient Receptor

In Duchenne muscular dystrophy (DMD) and in the mdx mouse model of DMD, the lack of dystrophin is related to enhanced calcium influx and muscle degeneration. Stretch-activated channels (SACs) might be directly involved in the pathology of DMD, and transient receptor potential cation channels have been proposed as likely candidates of SACs. We investigated the levels of transient receptor potential canonical channel 1 (TRPC1) and the effects of streptomycin, a SAC blocker, in muscles showing different degrees of the dystrophic phenotype. Mdx mice (18 days old, n = 16) received daily intraperitoneal injections of streptomycin (182 mg/kg body wt) for 18 days, followed by removal of the diaphragm, sternomastoid (STN), biceps brachii, and tibialis anterior muscles. Control mdx mice ( n = 37) were injected with saline. Western blot analysis showed higher levels of TRPC1 in diaphragm muscle compared with STN and limb muscles. Streptomycin reduced creatine kinase and prevented exercise-induced increases of total calcium and Evans blue dye uptake in diaphragm and in STN muscles. It is suggested that different levels of the stretch-activated calcium channel protein TRPC1 may contribute to the different degrees of the dystrophic phenotype seen in mdx mice. Early treatment designed to regulate the activity of these channels may ameliorate the progression of dystrophy in the most affected muscle, the diaphragm.

In situ study of the sarcoplasmic reticulum function in control and mdx mouse diaphragm muscle

1998 ◽  
Vol 76 (12) ◽  
pp. 1161-1165 ◽  
Author(s):  
A Khammari ◽  
Y Péréon ◽  
S Baudet ◽  
J Noireaud
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Recovery Process ◽  
Diaphragm Muscle ◽  
Calcium Handling ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
Time Interval ◽  
Similar Time ◽  
Rapid Cooling ◽  
Significant Difference

Sarcoplasmic reticulum (SR) calcium handling in diaphragm was compared between mdx mice (7-8 weeks old) and age-matched controls. The total SR Ca2+ load was released from the SR by rapidly cooling muscle bundles from 22 to -1°C. The plateau amplitude of the rapid cooling contracture (RCC) was considered as an index of the SR Ca2+ content. The steady-state RCC amplitude was significantly lower by 50% in mdx bundles mainly because of a decreased capacity of the dystrophic diaphragm to generate maximal tension. There was no significant difference between either RCC time to peak or the time to half-relaxation of the transient, spike-like, contractile response induced by muscle rewarming. The recovery process of RCC was studied by using a paired RCC protocol. In both groups, at the shortest interval (10 s) between two RCCs, the amplitude of the second RCC was decreased by 25% compared with the first RCC. Increasing the time interval led to progressive monoexponential recovery of the second RCC with similar time constants in control and mdx diaphragm. These results indicate that the dystrophic process does not significantly alter SR Ca2+ uptake nor Ca2+ redistribution within the muscular cell.Key words: diaphragm, mdx, rapid cooling contracture, sarcoplasmic reticulum.

Fine structure of early degenerating myofibers in the tibialis anterior of young ‘MDX’ mouse

1988 ◽  
Vol 46 ◽  
pp. 322-323
Author(s):  
H.D. Geissinger ◽  
C.K. McDonald-Taylor
Keyword(s):  
Fine Structure ◽  
Muscle Regeneration ◽  
Tibialis Anterior ◽  
Genetic Defect ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
Histopathological Changes ◽  
Electron Microscopic ◽  
Dystrophic Mouse ◽  
Preliminary Study

A new strain of mice, which had arisen by mutation from a dystrophic mouse colony was designated ‘mdx’, because the genetic defect, which manifests itself in brief periods of muscle destruction followed by episodes of muscle regeneration appears to be X-linked. Further studies of histopathological changes in muscle from ‘mdx’ mice at the light microscopic or electron microscopic levels have been published, but only one preliminary study has been on the tibialis anterior (TA) of ‘mdx’ mice less than four weeks old. Lesions in the ‘mdx’ mice vary between different muscles, and centronucleation of fibers in all muscles studied so far appears to be especially prominent in older mice. Lesions in young ‘mdx’ mice have not been studied extensively, and the results appear to be at variance with one another. The degenerative and regenerative aspects of the lesions in the TA of 23 to 26-day-old ‘mdx’ mice appear to vary quantitatively.

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