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

Xiaodong Zou,Xiaochun Tang,Hongsheng Ouyang,Daxin Pang,Renzhi Han

doi:10.1186/s13578-021-00647-9

Abstract

BackgroundPatients 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.ResultsHere 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.ConclusionsThis 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.

Highlights

Duchenne muscular dystrophy (DMD), inherited in an X-linked recessive manner, is a severe and progressive neuromuscular disorder [1], and its prevalence in the general population is approximately 1/5000 [2, 3]
Zou et al Cell Biosci (2021) 11:131 smooth muscle fibrosis was found in the entire GI tract of the DMD patients with intestinal pseudo-obstruction, and it was most obvious in the esophagus and stomach [12]
The on-target editing efficiency of this single guide RNA (sgRNA) was assessed by Sanger sequencing of the target site PCR amplicon following electroporation into porcine fetal fibroblasts (PFFs)

Summary

Introduction

Duchenne muscular dystrophy (DMD), inherited in an X-linked recessive manner, is a severe and progressive neuromuscular disorder [1], and its prevalence in the general population is approximately 1/5000 [2, 3]. Progressive muscle injury and degeneration in DMD patients leads to muscular weakness, loss of ambulation, respiratory impairment, and cardiomyopathy [4]. The clinical and pathological progression of skeletal muscle and myocardium involvement can be variable, death usually occurs around the age of 30 years due to cardiac and/or respiratory failure [5]. Previous clinical studies reported that impaired GI smooth muscle functions cause acute gastric dilatation in DMD patients. Patients with Duchenne muscular dystrophy (DMD) develop severe skeletal and cardiac muscle pathologies, which result in premature death. How the pathological alterations in gastrointestinal tissues contribute to the disease are not fully explored

Methods

Results

Conclusion