The metabolomic plasma profile of patients with Duchenne muscular dystrophy: providing new evidence for its pathogenesis

Abstract

Background: Duchenne muscular dystrophy (DMD) is a fatal genetic muscle-wasting disease that affects 1 in 5000 male births with no current cure. Despite great progress has been made in the research of DMD, its underlying pathological mechanism based on the metabolomics is still worthy of further study. Therefore, it is necessary to gain a deeper understanding of the mechanisms or pathogenesis underlying DMD, which may reveal potential therapeutic targets and/or biomarkers.

Results: Plasma samples from 42 patients with DMD from a natural history study and 40 age-matched healthy volunteers were subjected to a liquid chromatography-mass spectrometry-based non-targeted metabolomics approach. Acquired metabolic data were evaluated by principal component analysis, partial least squares-discriminant analysis, and metabolic pathway analysis to explore distinctive metabolic patterns in patients with DMD. Differentially expressed metabolites were identified using publicly available and integrated databases. By comparing the DMD and healthy control groups, 25 differential metabolites were detected, including amino acids, unsaturated fatty acids, carnitine, lipids, and metabolites related to the gut microbiota. Correspondingly, linoleic acid metabolism, D-glutamine and D-glutamate metabolism, glycerophospholipid metabolism, and alanine, aspartate, and glutamate metabolism were significantly altered in patients with DMD, compared with those of healthy volunteers.

Conclusions: Our study demonstrated the abnormal metabolism of amino acids, energy, and lipids in patients with DMD, consistent with pathological features, such as recurrent muscle necrosis and regeneration, interstitial fibrosis, and fat replacement. Additionally, we found that metabolites of intestinal flora were disordered in DMD patients, providing support for treatment of intestinal microbia disturbance in DMD diseases. Our study provides a new research strategy for understanding the pathogenesis of DMD.

Keywords: Duchenne muscular dystrophy; Mass spectrometry; Metabonomics; Plasma.

Fig. 1

PCA score plots and correlation analysis of QC samples in ESI+ (A, C) and ESI− (B, D) scan modes

Fig. 2

Plots of PCA (A, B) and PLS-DA scores (C, D) with permutation testing (E, F) for healthy controls and DMD patients comparison in the ESI + and ESI − scan modes

Fig. 3

Differential metabolite heat maps in ESI+ (A) and ESI− (B) scan modes. The columns represent samples, the rows represent metabolites, and the relative content of the metabolites is displayed by color

Fig. 4

The box plot of normalized intensity peak areas of significantly changed metabolites in DMD group when compared with HC group. Red represent the DMD group, and blue represent the HC group

Fig. 5

Bubble diagram of metabolic pathways between DMD and HC groups