C–X–C motif chemokine ligand 12: a potential therapeutic target in Duchenne muscular dystrophy

ABSTRACT

Duchenne muscular dystrophy (DMD) is an X-linked recessive disease caused by a mutant dystrophin protein. DMD patients undergo gradual progressive paralysis until death. Chronic glucocorticoid therapy remains one of the main treatments for DMD, despite the significant side effects. However, its mechanisms of action remain largely unknown. We used bioinformatics tools to identify pathogenic genes involved in DMD and glucocorticoid target genes. Two gene expression profiles containing data from DMD patients and healthy controls (GSE38417 and GSE109178) were downloaded for further analysis. Differentially expressed genes (DEGs) between DMD patients and controls were identified using GEO2R, and glucocorticoid target genes were predicted from the Pharmacogenetics and Pharmacogenomics Knowledge Base. Surprisingly, only one gene, CXCL12 (C–X–C motif chemokine ligand 12), was both a glucocorticoid target and a DEG. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis, Gene Ontology term enrichment analysis, and gene set enrichment analysis were performed. A protein–protein interaction network was constructed and hub genes identified using the Search Tool for the Retrieval of Interacting Genes (STRING) database and Cytoscape. Enriched pathways involving the DEGs, including CXCL12, were associated with the immune response and inflammation. Levels of CXCL12 and its receptor CXCR4 (C–X–C motif chemokine receptor 4) were increased in X-linked muscular dystrophy (mdx) mice (DMD models) but became significantly reduced after prednisone treatment. Metformin also reduced the expression of CXCL12 and CXCR4 in mdx mice. In conclusion, the CXCL12–CXCR4 pathway may be a potential target for DMD therapy.

KEYWORDS:

• Duchenne muscular dystrophy
• bioinformatic analysis
• differentially expressed genes
• cxcl12
• glucocorticoids

Highlights

1. Differentially expressed genes (DEGs) between DMD patients and healthy human controls were identified and analyzed.

2. CXCL12 is the only one of these DEGs that is also a predicted glucocorticoid target gene.

3. CXCL12 and its receptor CXCR4 showed increased expression in DMD mouse models (mdx mice).

Availability of data and materials

The datasets were acquired from the National Center for Biotechnology Information Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/) and the Pharmacogenetics and Pharmacogenomics Knowledge Base (PharmGKB) database (https://www.pharmgkb.org).

Abbreviations

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Disclosure statement

The authors declare that they have no competing interests.

Author contributions

JC and XL designed the research; JC performed the experiments and analyzed the data; JC and XL wrote the manuscript. All authors read and approved the final manuscript.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (31660268 and 81601092) and the Natural Science Foundation of Jiangxi Province (20181BAB215017).