Contractile function and low-intensity exercise effects of old dystrophic (mdx) mice

1998 ◽  
Vol 274 (4) ◽  
pp. C1138-C1144 ◽  
Author(s):  
Alan Hayes ◽  
David A. Williams
Keyword(s):  
Muscular Dystrophy ◽  
Contractile Function ◽  
Weight Bearing ◽  
Contractile Properties ◽  
Mdx Mice ◽  
Type I ◽  
Dystrophic Muscle ◽  
Low Intensity ◽  
Duchenne's Muscular Dystrophy ◽  
Low Intensity Exercise

Old mdx mice display a severe myopathy almost identical to Duchenne’s muscular dystrophy. This study examined the contractile properties of old mdxmuscles and investigated any effects of low-intensity exercise. Isometric contractile properties of the extensor digitorum longus (EDL) and soleus muscles were tested in adult (8–10 mo) and old (24 mo, split into sedentary and exercised groups) mdx mice. The EDL and soleus from old mdx mice exhibited decreased absolute twitch and tetanic forces, and the soleus exhibited a >50% decrease in relative forces (13.4 ± 0.4 vs. 6.0 ± 0.9 N/cm2) compared with adult mice. Old mdx muscles also showed longer contraction times and a higher percentage of type I fibers. Normal and mdx mice completed 10 wk of swimming, but mdx mice spent significantly less time swimming than normal animals (7.8 ± 0.4 vs. 15.8 ± 1.1 min, respectively). However, despite their severe dystrophy, mdx muscles responded positively to the low-intensity exercise. Relative tetanic tensions were increased (∼25% and ∼45% for the EDL and soleus, respectively) after the swimming, although absolute forces were unaffected. Thus these results indicate that, even with a dystrophin-deficient myopathy, mdx muscles can still respond to low-intensity exercise. This study shows that the contractile function of muscles of old mdx mice displays many similarities to that of human dystrophic patients and provides further evidence that the use of non-weight-bearing, low-intensity exercises, such as swimming, has no detrimental effect on dystrophic muscle and could be a useful therapeutic aid for sufferers of muscular dystrophy.

Effect of Early Low-Intensity Exercise on Rat Hind-Limb Muscles Following Acute Ischemic Stroke

2006 ◽  
Vol 7 (3) ◽  
pp. 163-174 ◽  
Author(s):  
Myoung-Ae Choe ◽  
Gyeong Ju An ◽  
Yoon-Kyong Lee ◽  
Ji Hye Im ◽  
Smi Choi-Kwon ◽  
...  
Keyword(s):  
Hind Limb ◽  
Gastrocnemius Muscle ◽  
Exercise Group ◽  
Cross Sectional Area ◽  
Type I ◽  
Sectional Area ◽  
Muscle Type ◽  
Cross Sectional ◽  
Low Intensity ◽  
Low Intensity Exercise

This study examined the effects of daily low-intensity exercise following acute stroke on mass, Type I and II fiber cross-sectional area, and myofibrillar protein content of hind-limb muscles in a rat model. Adult male Sprague-Dawley rats were randomly assigned to 1 of 4 groups (n = 7-9 per group): stroke (occlusion of the right middle cerebral artery [RMCA]), control (sham RMCA procedure), exercise, and stroke-exercise. Beginning 48 hours post-stroke induction/sham operation, rats in the exercise group had 6 sessions of exercise in which they ran on a treadmill at grade 10 for 20 min/day at 10 m/min. At 8 days poststroke, all rats were anesthetized and soleus, plantaris, and gastrocnemius muscles were dissected from both the affected and unaffected sides. After 6 sessions of exercise following acute ischemic stroke, the stroke-exercise group showed the following significant (p < .05) increases compared to the stroke-only group: body weight and dietary intake, muscle weight of affected soleus and both affected and unaffected gastrocnemius muscle, Type I fiber cross-sectional area of affected soleus and both affected and unaffected gastrocnemius muscle, Type II fiber cross-sectional area of the unaffected soleus, both affected and unaffected plantaris and gastrocnemius muscle, Type II fiber distribution of affected gastrocnemius muscle, and myofibrillar protein content of both affected and unaffected soleus muscle. Daily low-intensity exercise following acute stroke attenuates hind-limb muscle atrophy in both affected and unaffected sides. The effects of exercise are more pronounced in the soleus and gastrocnemius as compared to the plantaris muscle.

scholarly journals Improvement of Endurance of DMD Animal Model Using Natural Polyphenols

2015 ◽  
Vol 2015 ◽  
pp. 1-17 ◽  
Author(s):  
Clementina Sitzia ◽  
Andrea Farini ◽  
Federica Colleoni ◽  
Francesco Fortunato ◽  
Paola Razini ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Genetic Defect ◽  
Premature Death ◽  
Mdx Mice ◽  
Dystrophic Muscle ◽  
Muscle Fibrosis ◽  
Natural Polyphenols ◽  
Dystrophin Deficiency ◽  
Force Reduction ◽  
Muscular Architecture

Duchenne muscular dystrophy (DMD), the most common form of muscular dystrophy, is characterized by muscular wasting caused by dystrophin deficiency that ultimately ends in force reduction and premature death. In addition to primary genetic defect, several mechanisms contribute to DMD pathogenesis. Recently, antioxidant supplementation was shown to be effective in the treatment of multiple diseases including muscular dystrophy. Different mechanisms were hypothesized such as reduced hydroxyl radicals, nuclear factor-κB deactivation, and NO protection from inactivation. Following these promising evidences, we investigated the effect of the administration of a mix of dietary natural polyphenols (ProAbe) on dystrophic mdx mice in terms of muscular architecture and functionality. We observed a reduction of muscle fibrosis deposition and myofiber necrosis together with an amelioration of vascularization. More importantly, the recovery of the morphological features of dystrophic muscle leads to an improvement of the endurance of treated dystrophic mice. Our data confirmed that ProAbe-based diet may represent a strategy to coadjuvate the treatment of DMD.

scholarly journals Evidence for impaired neurovascular transmission in a murine model of Duchenne muscular dystrophy

2011 ◽  
Vol 110 (3) ◽  
pp. 601-609 ◽  
Author(s):  
Pooneh Bagher ◽  
Dongsheng Duan ◽  
Steven S. Segal
Keyword(s):  
Blood Flow ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Nerve Stimulation ◽  
Murine Model ◽  
Dystrophin Gene ◽  
Mdx Mice ◽  
Response Curves ◽  
Dystrophic Muscle ◽  
Neurovascular Transmission

Duchenne muscular dystrophy (DMD) is a muscle-wasting disease caused by mutations in the dystrophin gene. Little is known about how blood flow control is affected in arteriolar networks supplying dystrophic muscle. We tested the hypothesis that mdx mice, a murine model for DMD, exhibit defects in arteriolar vasomotor control. The cremaster muscle was prepared for intravital microscopy in pentobarbital sodium-anesthetized mdx and C57BL/10 control mice ( n ≥ 5 per group). Spontaneous vasomotor tone increased similarly with arteriolar branch order in both mdx and C57BL/10 mice [pooled values: first order (1A), 6%; second order (2A), 56%; and third order (3A), 61%] with no difference in maximal diameters between groups measured during equilibration with topical 10 μM sodium nitroprusside (pooled values: 1A, 70 ± 3 μm; 2A, 31 ± 3 μm; and 3A, 19 ± 3 μm). Concentration-response curves to acetylcholine (ACh) and norepinephrine added to the superfusion solution did not differ between mdx and C57BL/10 mice, nor did constriction to elevated (21%) oxygen. In response to local stimulation from a micropipette, conducted vasodilation to ACh and conducted vasoconstriction to KCl were also not different between groups; however, constriction decayed with distance ( P < 0.05) whereas dilation did not. Remarkably, arteriolar constriction to perivascular nerve stimulation (PNS) at 2, 4, and 8 Hz was reduced by ∼25–30% in mdx mice compared with C57BL/10 mice ( P < 0.05). With intact arteriolar reactivity to agonists, attenuated constriction to perivascular nerve stimulation indicates impaired neurovascular transmission in arterioles controlling blood flow in mdx mice.

Adaptations in myosin heavy chain expression and contractile function in dystrophic mouse diaphragm

1993 ◽  
Vol 265 (3) ◽  
pp. C834-C841 ◽  
Author(s):  
B. J. Petrof ◽  
H. H. Stedman ◽  
J. B. Shrager ◽  
J. Eby ◽  
H. L. Sweeney ◽  
...  
Keyword(s):  
Myosin Heavy Chain ◽  
Heavy Chain ◽  
Contractile Function ◽  
Isometric Tension ◽  
Energy Requirements ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
Type I ◽  
Muscle Degeneration ◽  
Cellular Energy

The X chromosome-linked muscular dystrophic (mdx) mouse lacks the subsarcolemmal protein dystrophin and thus represents a genetic homologue of human Duchenne muscular dystrophy. The present study examined alterations in diaphragm contractile properties and myosin heavy chain (MHC) expression in young (3-4 mo) and old (22-24 mo) control and mdx mice. In young mdx mice, maximum isometric tension (Po) was reduced to 50% of control values. An increase in fibers coexpressing types I (slow) and IIa MHC as well as regenerating fibers expressing embryonic MHC occurred, whereas IIx/b fibers were decreased. In the old mdx group, Po underwent a further reduction to 25% of control, and there was a slowing of twitch kinetics along with markedly increased diaphragm endurance. These changes were associated with an approximate sevenfold increase in type I MHC fibers and virtual elimination of the IIx/b fiber population; there was no detectable embryonic MHC expression. We conclude that the mdx diaphragm responds to progressive muscle degeneration with transition to a slower phenotype associated with reduced power output and augmented muscle endurance. In the setting of progressive muscle fiber destruction, these changes may help preserve contractile function and promote greater survival of remaining muscle fibers by decreasing cellular energy requirements.

scholarly journals A nitric oxide synthase transgene ameliorates muscular dystrophy in mdx mice

2001 ◽  
Vol 155 (1) ◽  
pp. 123-132 ◽  
Author(s):  
Michelle Wehling ◽  
Melissa J. Spencer ◽  
James G. Tidball
Keyword(s):  
Nitric Oxide ◽  
Muscular Dystrophy ◽  
Nitric Oxide Synthase ◽  
Muscle Membrane ◽  
Mdx Mice ◽  
No Production ◽  
Dystrophic Muscle ◽  
Membrane Injury ◽  
Oxide Synthase

Dystrophin-deficient muscles experience large reductions in expression of nitric oxide synthase (NOS), which suggests that NO deficiency may influence the dystrophic pathology. Because NO can function as an antiinflammatory and cytoprotective molecule, we propose that the loss of NOS from dystrophic muscle exacerbates muscle inflammation and fiber damage by inflammatory cells. Analysis of transgenic mdx mice that were null mutants for dystrophin, but expressed normal levels of NO in muscle, showed that the normalization of NO production caused large reductions in macrophage concentrations in the mdx muscle. Expression of the NOS transgene in mdx muscle also prevented the majority of muscle membrane injury that is detectable in vivo, and resulted in large decreases in serum creatine kinase concentrations. Furthermore, our data show that mdx muscle macrophages are cytolytic at concentrations that occur in dystrophic, NOS-deficient muscle, but are not cytolytic at concentrations that occur in dystrophic mice that express the NOS transgene in muscle. Finally, our data show that antibody depletions of macrophages from mdx mice cause significant reductions in muscle membrane injury. Together, these findings indicate that macrophages promote injury of dystrophin-deficient muscle, and the loss of normal levels of NO production by dystrophic muscle exacerbates inflammation and membrane injury in muscular dystrophy.

Contractile efficiency of dystrophic mdx mouse muscle: in vivo and ex vivo assessment of adaptation to exercise of functional end points

2017 ◽  
Vol 122 (4) ◽  
pp. 828-843 ◽  
Author(s):  
Roberta Francesca Capogrosso ◽  
Paola Mantuano ◽  
Anna Cozzoli ◽  
Francesca Sanarica ◽  
Ada Maria Massari ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Muscle Damage ◽  
Functional Adaptation ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
Chronic Exercise ◽  
Exercise Protocol ◽  
Dystrophic Muscle

Progressive weakness is a typical feature of Duchenne muscular dystrophy (DMD) patients and is exacerbated in the benign mdx mouse model by in vivo treadmill exercise. We hypothesized a different threshold for functional adaptation of mdx muscles in response to the duration of the exercise protocol. In vivo weakness was confirmed by grip strength after 4, 8, and 12 wk of exercise in mdx mice. Torque measurements revealed that exercise-related weakness in mdx mice correlated with the duration of the protocol, while wild-type (WT) mice were stronger. Twitch and tetanic forces of isolated diaphragm and extensor digitorum longus (EDL) muscles were lower in mdx compared with WT mice. In mdx, both muscle types exhibited greater weakness after a single exercise bout, but only in EDL after a long exercise protocol. As opposite to WT muscles, mdx EDL ones did not show any exercise-induced adaptations against eccentric contraction force drop. qRT-PCR analysis confirmed the maladaptation of genes involved in metabolic and structural remodeling, while damage-related genes remained significantly upregulated and angiogenesis impaired. Phosphorylated AMP kinase level increased only in exercised WT muscle. The severe histopathology and the high levels of muscular TGF-β1 and of plasma matrix metalloproteinase-9 confirmed the persistence of muscle damage in mdx mice. Therefore, dystrophic muscles showed a partial degree of functional adaptation to chronic exercise, although not sufficient to overcome weakness nor signs of damage. The improved understanding of the complex mechanisms underlying maladaptation of dystrophic muscle paves the way to a better managment of DMD patients. NEW & NOTEWORTHY We focused on the adaptation/maladaptation of dystrophic mdx mouse muscles to a standard protocol of exercise to provide guidance in the development of more effective drug and physical therapies in Duchenne muscular dystrophy. The mdx muscles showed a modest functional adaptation to chronic exercise, but it was not sufficient to overcome the progressive in vivo weakness, nor to counter signs of muscle damage. Therefore, a complex involvement of multiple systems underlies the maladaptive response of dystrophic muscle.

scholarly journals uPA deficiency exacerbates muscular dystrophy in MDX mice

2007 ◽  
Vol 178 (6) ◽  
pp. 1039-1051 ◽  
Author(s):  
Mònica Suelves ◽  
Berta Vidal ◽  
Antonio L. Serrano ◽  
Marc Tjwa ◽  
Josep Roma ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Inflammatory Cells ◽  
Mdx Mice ◽  
Muscle Dystrophy ◽  
Dystrophic Muscle ◽  
Critical Function ◽  
Upa Receptor ◽  
Muscular Function ◽  
Degenerative Disorder ◽  
Transplantation Experiments

Duchenne muscular dystrophy (DMD) is a fatal and incurable muscle degenerative disorder. We identify a function of the protease urokinase plasminogen activator (uPA) in mdx mice, a mouse model of DMD. The expression of uPA is induced in mdx dystrophic muscle, and the genetic loss of uPA in mdx mice exacerbated muscle dystrophy and reduced muscular function. Bone marrow (BM) transplantation experiments revealed a critical function for BM-derived uPA in mdx muscle repair via three mechanisms: (1) by promoting the infiltration of BM-derived inflammatory cells; (2) by preventing the excessive deposition of fibrin; and (3) by promoting myoblast migration. Interestingly, genetic loss of the uPA receptor in mdx mice did not exacerbate muscular dystrophy in mdx mice, suggesting that uPA exerts its effects independently of its receptor. These findings underscore the importance of uPA in muscular dystrophy.

scholarly journals Amelioration of muscular dystrophy phenotype in mdx mice by inhibition of Flt1

2019 ◽  
Author(s):  
Mayank Verma ◽  
Yuko Shimizu-Motohashi ◽  
Yoko Asakura ◽  
James Ennen ◽  
Jennifer Bosco ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Muscular Dystrophy ◽  
Knockout Mice ◽  
Gene Knockout ◽  
Functional Improvement ◽  
Mdx Mice ◽  
Vascular Density ◽  
Dystrophic Muscle ◽  
Skeletal Muscle Function ◽  
Vegf Signaling

AbstractDuchenne muscular dystrophy (DMD) is an X-linked recessive genetic disease in which the dystrophin coding for a membrane stabilizing protein is mutated. Recently, the vasculature has also shown to be perturbed in DMD and DMD model mdx mice. Data-mining DMD transcriptomics revealed the defects were correlated to a vascular endothelial growth factor (VEGF) signaling pathway. To reveal the relationship between DMD and VEGF signaling, mdx mice were crossed with constitutive (CAG/CreERTM:Flt1LoxP/LoxP) and endothelial cell-specific conditional gene knockout mice (Cdh5CreERT2:Flt1LoxP/LoxP) for Flt1 which is a decoy receptor for VEGF. Previous work demonstrated that heterozygous global Flt1 knockout mice increased vascular density and improved DMD phenotypes when crossed with DMD model mdx and mdx:utrn-/- mice. Here, we showed that while constitutive deletion of Flt1 is detrimental to the skeletal muscle function, endothelial cell-specific Flt1 deletion resulted in increased vascular density and improvement in the DMD-associated phenotype in the mdx mice. These decreases in pathology, including improved muscle histology and function, were recapitulated in mdx mice given anti-FLT1 peptides or monoclonal antibodies, which blocked VEGF-FLT1 binding. The histological and functional improvement of dystrophic muscle by FLT1 blockade provides a novel pharmacological strategy for the potential treatment of DMD.

Engineered early embryonic cardiac tissue retains proliferative and contractile properties of developing embryonic myocardium

2006 ◽  
Vol 291 (4) ◽  
pp. H1829-H1837 ◽  
Author(s):  
Kimimasa Tobita ◽  
Li J. Liu ◽  
Andrzej M. Janczewski ◽  
Joseph P. Tinney ◽  
Jill M. Nonemaker ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cellular Proliferation ◽  
Cardiac Tissue ◽  
Contractile Function ◽  
3D Structure ◽  
Contractile Properties ◽  
High Rate ◽  
Type I ◽  
Tissue Architecture ◽  
Ventricular Cells

Embryonic myocardium has a high rate of cell proliferation and regulates cellular proliferation, contractile function, and myocardial architecture in response to changes in external mechanical loads. However, the small and complex three-dimensional (3D) structure of the embryonic myocardium limits our ability to directly investigate detailed relationships between mechanical load, contractile function, and cardiomyocyte proliferation. We developed a novel 3D engineered early embryonic cardiac tissue (EEECT) from early embryonic ventricular cells to test the hypothesis that EEECT retains the proliferative and contractile properties of embryonic myocardium. We combined freshly isolated White Leghorn chicken embryonic ventricular cells at Hamburger-Hamilton (HH) stage 31 ( day 7 of a 46-stage, 21-day incubation period), collagen type I, and matrix factors to construct cylindrical-shaped EEECTs. We studied tissue architecture, cell proliferation patterns, and contractile function. We then generated engineered fetal cardiac tissue (EFCT) from HH stage 40 ( day 14) fetal ventricular cells for direct comparison with EEECT. Tissue architecture was similar in EEECT and EFCT. EEECT maintained high cell proliferation patterns by culture day 12, whereas EFCT decreased cell proliferation rate by culture day 9 ( P < 0.05). EEECT increased active contractile force from culture day 7 to day 12. The culture day 12 EEECT contractile response to the β-adrenergic stimulation was less than culture day 9 EFCT ( P < 0.05). Cyclic mechanical stretch stimulation induced myocardial hyperplasia in EEECT. Results indicate that EEECT retains the proliferative and contractile properties of developing embryonic myocardium and shows potential as a robust in vitro model of developing embryonic myocardium.

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