Pathological alterations in the gastrointestinal tract of a porcine model of DMD

Abstract Background Patients with Duchenne muscular dystrophy (DMD) develop severe skeletal and cardiac muscle pathologies, which result in premature death. Therefore, the current therapeutic efforts are mainly targeted to correct dystrophin expression in skeletal muscle and heart. However, it was reported that DMD patients may also exhibit gastrointestinal and nutritional problems. How the pathological alterations in gastrointestinal tissues contribute to the disease are not fully explored. Results Here we employed the CRISPR/Cas9 system combined with somatic nuclear transfer technology (SCNT) to establish a porcine model of DMD and explored their pathological alterations. We found that genetic disruption of dystrophin expression led to morphological gastrointestinal tract alterations, weakened the gastrointestinal tract digestion and absorption capacity, and eventually led to malnutrition and gastric dysfunction in the DMD pigs. Conclusions This work provides important insights into the pathogenesis of DMD and highlights the need to consider the gastrointestinal dysfunction as an additional therapeutic target for DMD patients.

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Pathological Alterations in the Gastrointestinal Tract of a Porcine Model of DMD

10.21203/rs.3.rs-267849/v1 ◽

2021 ◽

Author(s):

Xiaodong Zhou ◽

Hongsheng Ouyang ◽

Daxin Pang ◽

Renzhi Han ◽

Xiaochun Tang

Keyword(s):

Skeletal Muscle ◽

Gastrointestinal Tract ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Nuclear Transfer ◽

Porcine Model ◽

Premature Death ◽

Absorption Capacity ◽

Gastrointestinal Dysfunction ◽

Dystrophin Expression

Abstract Patients with Duchenne muscular dystrophy (DMD) develop severe skeletal and cardiac muscle pathologies, which result in premature death. Therefore, the current therapeutic efforts are mainly targeted to correct dystrophin expression in skeletal muscle and heart. However, it was reported that DMD patients may also exhibit gastrointestinal and nutritional problems. How the pathological alterations in gastrointestinal tissues may contribute to the disease are not fully explored. Here we employed the CRISPR/Cas9 system combined with somatic nuclear transfer technology (SCNT) to establish a porcine model of DMD and explored their pathological alterations. We found that genetic disruption of dystrophin expression led1 to morphological gastrointestinal tract alterations, weakened the gastrointestinal tract digestion and absorption capacity, and eventually led to malnutrition and gastric dysfunction in the DMD pigs. This work provides important insights into the pathogenesis of DMD and highlights the need to consider the gastrointestinal dysfunction as an additional therapeutic target for DMD patients.

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Reversal of cardiac and skeletal manifestations of Duchenne muscular dystrophy by cardiosphere-derived cells and their exosomes in mdx dystrophic mice and in human Duchenne cardiomyocytes

10.1101/128900 ◽

2017 ◽

Cited By ~ 4

Author(s):

Mark A. Aminzadeh ◽

Russell G. Rogers ◽

Kenneth Gouin ◽

Mario Fournier ◽

Rachel E. Tobin ◽

...

Keyword(s):

Skeletal Muscle ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Mouse Model ◽

Cardiac Function ◽

Premature Death ◽

Next Generation ◽

Skeletal Myopathy ◽

Genetic Deficiency ◽

Dystrophic Mice

Genetic deficiency of dystrophin leads to disability and premature death in Duchenne muscular dystrophy, affecting the heart as well as skeletal muscle. Here we report that cardiosphere-derived cells (CDCs), which are being tested clinically for the treatment of Duchenne cardiomyopathy, improve cardiac and skeletal myopathy in the mdx mouse model of DMD and in human Duchenne cardiomyocytes. Injection of CDCs into the hearts of mdx mice augments cardiac function, ambulatory capacity and survival. Exosomes secreted by human CDCs reproduce the benefits of CDCs in mdx mice and in human Duchenne cardiomyocytes. The findings further motivate the testing of CDCs in Duchenne patients, while identifying exosomes as next-generation therapeutic candidates.

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The Role of Exercise as a Therapy for Children with Duchenne Muscular Dystrophy

Pediatric Exercise Science ◽

10.1123/pes.12.1.23 ◽

2000 ◽

Vol 12 (1) ◽

pp. 23-33 ◽

Cited By ~ 3

Author(s):

Stephen P. Sayers

Keyword(s):

Quality Of Life ◽

Physical Activity ◽

Skeletal Muscle ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Premature Death ◽

Risks And Benefits ◽

Progressive Weakness

Duchenne muscular dystrophy (DMD) is a disease affecting muscle fiber integrity in boys that leads to progressive weakness in skeletal muscle and premature death. Currently, there is no known cure for the disease. Different interventions have been explored to delay the progression of the disease and improve the quality of life for the DMD patient. Physical activity is one treatment that has generated controversy due to the increased mechanical stress placed on the muscle during contraction. This review explores the literature in animal models and human DMD patients and evaluates the known theoretical risks and benefits of increased physical activity in DMD patients.

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Faculty Opinions recommendation of microRNA-206 promotes skeletal muscle regeneration and delays progression of Duchenne muscular dystrophy in mice.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717397850.793153110 ◽

2012 ◽

Author(s):

Michael Rudnicki ◽

Alessandra Pasut

Keyword(s):

Skeletal Muscle ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Muscle Regeneration ◽

Skeletal Muscle Regeneration

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Autophagy in the heart is enhanced and independent of disease progression in mus musculus dystrophinopathy models

JRSM Cardiovascular Disease ◽

10.1177/2048004019879581 ◽

2019 ◽

Vol 8 ◽

pp. 204800401987958

Author(s):

HR Spaulding ◽

C Ballmann ◽

JC Quindry ◽

MB Hudson ◽

JT Selsby

Keyword(s):

Skeletal Muscle ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Disease Progression ◽

Gene Mutations ◽

Dystrophin Gene ◽

Mdx Mice ◽

Dystrophin Deficiency ◽

Muscle Wasting Disease ◽

Dystrophin Protein

Background Duchenne muscular dystrophy is a muscle wasting disease caused by dystrophin gene mutations resulting in dysfunctional dystrophin protein. Autophagy, a proteolytic process, is impaired in dystrophic skeletal muscle though little is known about the effect of dystrophin deficiency on autophagy in cardiac muscle. We hypothesized that with disease progression autophagy would become increasingly dysfunctional based upon indirect autophagic markers. Methods Markers of autophagy were measured by western blot in 7-week-old and 17-month-old control (C57) and dystrophic (mdx) hearts. Results Counter to our hypothesis, markers of autophagy were similar between groups. Given these surprising results, two independent experiments were conducted using 14-month-old mdx mice or 10-month-old mdx/Utrn± mice, a more severe model of Duchenne muscular dystrophy. Data from these animals suggest increased autophagosome degradation. Conclusion Together these data suggest that autophagy is not impaired in the dystrophic myocardium as it is in dystrophic skeletal muscle and that disease progression and related injury is independent of autophagic dysfunction.

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