Muscle metabolic remodelling patterns in Duchenne muscular dystrophy revealed by ultra-high-resolution mass spectrometry imaging

Ivana Dabaj,Abdellah Tebani,Soumeya Bekri,Catherine Vanhulle,Youssef Bahri,Isabelle Schmitz-Afonso,France Leturcq,Stéphane Marret,Carole Basset,Carlos Afonso,Anne-Claire Brehin,Florent Marguet,Vianney Gilard,Annie Laquerrière,Justine Ferey

doi:10.1038/s41598-021-81090-1

Abstract

Duchenne muscular dystrophy (DMD) is a common and severe X-linked myopathy, characterized by muscle degeneration due to altered or absent dystrophin. DMD has no effective cure, and the underlying molecular mechanisms remain incompletely understood. The aim of this study is to investigate the metabolic changes in DMD using mass spectrometry-based imaging. Nine human muscle biopsies from DMD patients and nine muscle biopsies from control individuals were subjected to untargeted MSI using matrix-assisted laser desorption/ionization Fourier-transform ion cyclotron resonance mass spectrometry. Both univariate and pattern recognition techniques have been used for data analysis. This study revealed significant changes in 34 keys metabolites. Seven metabolites were decreased in the Duchenne biopsies compared to control biopsies including adenosine triphosphate, and glycerophosphocholine. The other 27 metabolites were increased in the Duchenne biopsies, including sphingomyelin, phosphatidylcholines, phosphatidic acids and phosphatidylserines. Most of these dysregulated metabolites are tightly related to energy and phospholipid metabolism. This study revealed a deep metabolic remodelling in phospholipids and energy metabolism in DMD. This systems-based approach enabled exploring the metabolism in DMD in an unprecedented holistic and unbiased manner with hypothesis-free strategies.

Highlights

Duchenne muscular dystrophy (DMD) is a common and severe X-linked myopathy, characterized by muscle degeneration due to altered or absent dystrophin
Defective dystrophin is known to be the main alteration in the DMD etiology, metabolic impairment has been reported in several tissues such as the skeletal and cardiac muscles, liver and b rain[27]
Our results showed profound metabolic pathway remodelling in the muscles of DMD patients compared with the controls grouped in two distinct clusters corresponding to the upregulated and downregulated metabolites

Summary

Introduction

Duchenne muscular dystrophy (DMD) is a common and severe X-linked myopathy, characterized by muscle degeneration due to altered or absent dystrophin. Nine human muscle biopsies from DMD patients and nine muscle biopsies from control individuals were subjected to untargeted MSI using matrix-assisted laser desorption/ionization Fourier-transform ion cyclotron resonance mass spectrometry. Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy in children, with an incidence of 1 in 5000 live-born boys annually and an estimated prevalence of 15.9 per 100,000 boys in the USA and 19.5 per 100,000 boys in the U K1–3 This lethal X-linked recessive neuromuscular disorder is caused by mutations in the DMD gene resulting in absent or reduced functional dystrophin (DYS). Powerful new mass spectrometry instruments based on Fourier-transform ion cyclotron resonance (FTICR) offer better analytical performance in terms of resolution, sensitivity and s pecificity[24,25,26] This technology offers unprecedented exhaustive metabolome coverage and non-ambiguous molecular formula a ssignments[26]. Given the scope of the study and the high analytical superiority of the platform, this investigation allowed holistically parsing the complex metabolic remodelling in DMD tissues, revealing the DMD-associated molecular metabolic impairments and deregulations, aiming to open new avenues for deeper biological investigations to uncover new therapeutic targets, biomarkers and diagnostic tools

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Conclusion