Comparison of Experimental Protocols of Physical Exercise for <i>mdx</i> Mice and Duchenne Muscular Dystrophy Patients

Hyzewicz, Janek; Rüegg, Urs T.; Takeda, Shin’ichi

doi:10.3233/jnd-150106

Cited by 52 publications

(55 citation statements)

References 104 publications

(107 reference statements)

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“…Utrophin, a dystrophin-like protein, participates in DGC formation, stability, and function in the absence of dystrophin [3, 4], hence utrophin upregulation remains an area of intense research interest [5–8]. Utrophin transcription can be driven by the exercise-sensitive PGC-1α pathway [9], however, attempts to use various exercise modalities as interventions for DMD have been met with mixed results [10–13]. Direct activation of the PGC-1α pathway using transgenic and gene transfer approaches yields consistently positive results using both prevention and rescue paradigms [14–18].…”

Section: Introductionmentioning

confidence: 99%

Long-Term Quercetin Dietary Enrichment Partially Protects Dystrophic Skeletal Muscle

et al. 2016

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Duchenne muscular dystrophy (DMD) results from a genetic lesion in the dystrophin gene and leads to progressive muscle damage. PGC-1α pathway activation improves muscle function and decreases histopathological injury. We hypothesized that mild disease found in the limb muscles of mdx mice may be responsive to quercetin-mediated protection of dystrophic muscle via PGC-1α pathway activation. To test this hypothesis muscle function was measured in the soleus and EDL from 14 month old C57, mdx, and mdx mice treated with quercetin (mdxQ; 0.2% dietary enrichment) for 12 months. Quercetin reversed 50% of disease-related losses in specific tension and partially preserved fatigue resistance in the soleus. Specific tension and resistance to contraction-induced injury in the EDL were not protected by quercetin. Given some functional gain in the soleus it was probed with histological and biochemical approaches, however, in dystrophic muscle histopathological outcomes were not improved by quercetin and suppressed PGC-1α pathway activation was not increased. Similar to results in the diaphragm from these mice, these data suggest that the benefits conferred to dystrophic muscle following 12 months of quercetin enrichment were underwhelming. Spontaneous activity at the end of the treatment period was greater in mdxQ compared to mdx indicating that quercetin fed mice were more active in addition to engaging in more vigorous activity. Hence, modest preservation of muscle function (specific tension) and elevated spontaneous physical activity largely in the absence of tissue damage in mdxQ suggests dietary quercetin may mediate protection.

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Section: Introductionmentioning

confidence: 99%

Long-Term Quercetin Dietary Enrichment Partially Protects Dystrophic Skeletal Muscle

et al. 2016

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“…Dystrophic muscle is susceptible to injury-induced by exercise training and the effects of physical training on muscle fiber morphology are still controversial (Gianola et al;Hyzewicz et al, 2015). Most studies that have analyzed the treadmill training on mdx mice model used a high intensity of training.…”

Section: Discussionmentioning

confidence: 99%

“…Also, at this age there is an already described similarity of fibrosis and muscular deterioration between humans and mdx mice age-matched. See schematic Figure 1 plotted with these similarities between both species according to the literature (Briguet et al;Grounds et al, 2008;Barnabei et al, 2011;Hyzewicz et al, 2015). This research was approved by the Ethics Committee on Animal Use of the University Federal dos Vales do Jequitinhonha e Mucuri (CEUA/UFVJM), protocol number 017/2011.…”

Section: Methodsmentioning

confidence: 99%

“…The most used animal model for pre-clinical studies of DMD is the mdx mouse (Manning & O'Malley, 2015;Hyzewicz et al, 2015). The mdx mouse shows absence of dystrophin and has genetic and biochemical homology to humans DMD but its phenotype is considered mild (Manning & O'Malley).…”

mentioning

confidence: 99%

“…Trying to elucidate the best frequency, type and modality of exercise for DMD, the mdx mouse has been used to attest the effects of different modalities such as swimming, voluntary wheel running, Rota-rod® and motorized treadmill (Hyzewicz et al, 2015). These studies have brought some insight of what should, or should not be applied to skeletal dystrophic muscle but there is not a consensus once major of them use a high intensity training that exacerbates the progression of the disease and attest the efficacy of some method of intervention.…”

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confidence: 99%

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Low Intensity Training Provokes Adaptations on Muscle Fibrosis of a Muscular Dystrophy Model

et al. 2018

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SUMMARY:Duchenne muscular dystrophy (DMD) is a genetic neuromuscular disorder with progressive clinical signs until death, around the second decade of life. Mdx is the most used animal model to pre-clinical studies of DMD. Parameters of exercise on this muscular disease are still unknown. This research aimed to investigate if the low intensity treadmill training would exacerbate the markers of muscle injury, fibrosis, and the composition of the extracellular matrix by type I and III collagens of the mdx model. Dystrophic 11-week-old male mice were separated in exercised (mdxE, n=8) and sedentary (mdxC, n=8) groups. Wild-type mice were used as control (WT, n=8). Exercised group underwent a LIT protocol (9 m/min, 30min, 3days/week, 60 days) on a horizontal treadmill. Gastrocnemius muscle was collected at day 60 and processed to morphological and morphometric analyzes. Sedentary mdx animals presented inflammatory infiltrate and necrotic fibers. Histochemical analysis revealed that the perimysium of the mdxC group is organized into thick and clustered collagen fibers, which generates a larger area of intramuscular collagen fibers for these animals. Histomorphometry attested that fraction area of collagen fibers of mdxC group was higher than mdxE group (p=0.04) and mdxE group values similar to WT group (p=1.00). Centrally located nuclei fibers and the variance coefficient (VC) of minimal Feret's diameter was similar in mdxE and mdxC groups (p=1.00) and both groups presented higher mean values than WT group (p<0.00). Immunohistochemistry revealed the presence of type I collagen mainly in the mdxC group. LIT protocol had not exacerbated muscle injuries resulting from the dystrophindeficiency membrane fragility at the same time that had reduced the intramuscular collagen deposition. LIT had positively influenced these markers of dystrophic muscle injury on gastrocnemius muscle of mdx model.

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Long‐term human IgG treatment improves heart and muscle function in a mouse model of Duchenne muscular dystrophy

Zschüntzsch

Jouvenal

Zhang

et al. 2020

J cachexia sarcopenia muscle

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Background Duchenne muscular dystrophy (DMD) is a progressive muscle‐wasting disease caused by mutations in the dystrophin gene, which leads to structural instability of the dystrophin–glycoprotein‐complex with subsequent muscle degeneration. In addition, muscle inflammation has been implicated in disease progression and therapeutically addressed with glucocorticosteroids. These have numerous adverse effects. Treatment with human immunoglobulin G (IgG) improved clinical and para‐clinical parameters in the early disease phase in the well‐established mdx mouse model. The aim of the present study was to confirm the efficacy of IgG in a long‐term pre‐clinical study in mdx mice. Methods IgG (2 g/kg body weight) or NaCl solution as control was administered monthly over 18 months by intraperitoneal injection in mdx mice beginning at 3 weeks of age. Several clinical outcome measures including endurance, muscle strength, and echocardiography were assessed. After 18 months, the animals were sacrificed, blood was collected for analysis, and muscle samples were obtained for ex vivo muscle contraction tests, quantitative PCR, and histology. Results IgG significantly improved the daily voluntary running performance (1.9 m more total daily running distance, P < 0.0001) and slowed the decrease in grip strength by 0.1 mN, ( P = 0.018). IgG reduced fatigability of the diaphragm (improved ratio to maximum force by 0.09 ± 0.04, P = 0.044), but specific tetanic force remained unchanged in the ex vivo muscle contraction test. Cardiac function was significantly better after IgG, especially fractional area shortening ( P = 0.012). These results were accompanied by a reduction in cardiac fibrosis and the infiltration of T cells ( P = 0.0002) and macrophages ( P = 0.0027). In addition, treatment with IgG resulted in a significant reduction of the infiltration of T cells ( P ≤ 0.036) in the diaphragm, gastrocnemius, quadriceps, and a similar trend in tibialis anterior and macrophages ( P ≤ 0.045) in gastrocnemius, quadriceps, tibialis anterior, and a similar trend in the diaphragm, as well as a decrease in myopathic changes as reflected by a reduced central nuclear index in the diaphragm, tibialis anterior, and quadriceps ( P ≤ 0.002 in all). Conclusions The present study underscores the importance of an inflammatory contribution to the disease progression of DMD. The data demonstrate the long‐term efficacy of IgG in the mdx mouse. IgG is well tolerated by humans and could preferentially complement gene therapy in DMD. ...

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Comparison of Experimental Protocols of Physical Exercise for mdx Mice and Duchenne Muscular Dystrophy Patients

Cited by 52 publications

References 104 publications

Long-Term Quercetin Dietary Enrichment Partially Protects Dystrophic Skeletal Muscle

Long-Term Quercetin Dietary Enrichment Partially Protects Dystrophic Skeletal Muscle

Low Intensity Training Provokes Adaptations on Muscle Fibrosis of a Muscular Dystrophy Model

Long‐term human IgG treatment improves heart and muscle function in a mouse model of Duchenne muscular dystrophy

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