Platelet Derived Growth Factor-AA Correlates With Muscle Function Tests and Quantitative Muscle Magnetic Resonance in Dystrophinopathies

Alicia Alonso‐Jiménez ,Patricia Piñol-Jurado,Isabel Illa,Izaskun Belmonte,Paula Montesinos,Irene Pedrosa,Daniel Natera-De Benito,Sonia Segovia,Jaume Llauger,Eduard Gallardo,Elena Montiel,Esther Fernández‐Simón ,C Jiménez-Mallebrera ,Jorge Alonso‐Pérez ,Claudia Nuñez‐Peralta ,Ana Carrasco‐Rozas ,Xavier Suárez‐Calvet ,C Ortez ,Carmen García ,A Nascimento ,Jordi Díaz‐Manera

doi:10.3389/fneur.2021.659922

Abstract

Introduction: Duchenne (DMD) and Becker (BMD) muscular dystrophy are X-linked muscular disorders produced by mutations in the DMD gene which encodes the protein dystrophin. Both diseases are characterized by progressive involvement of skeletal, cardiac, and respiratory muscles. As new treatment strategies become available, reliable biomarkers and outcome measures that can monitor disease progression are needed for clinical trials.Methods: We collected clinical and functional data and blood samples from 19 DMD patients, 13 BMD patients, and 66 healthy controls (8 pediatric and 58 adult controls), and blood samples from 15 patients with dysferlinopathy (DYSF) and studied the serum concentration of 4 growth factors involved in the process of muscle fibrosis. We correlated the serum concentration of these growth factors with several muscle function tests, spirometry results and fat fraction identified by quantitative Dixon muscle MRI.Results: We found significant differences in the serum concentration of Platelet Derived Growth Factor-AA (PDGF-AA) between DMD patients and pediatric controls, in Connective Tissue Growth Factor (CTGF) between BMD patients and adult controls, and in and Transforming Growth Factor- β1 (TGF-β1) between BMD and DYSF patients. PDGF-AA showed a good correlation with several muscle function tests for both DMD and BMD patients and with thigh fat fraction in BMD patients. Moreover, PDGF-AA levels were increased in muscle biopsies of patients with DMD and BMD as was demonstrated by immunohistochemistry and Real-Time PCR studies.Conclusion: Our study suggests that PDGF-AA should be further investigated in a larger cohort of DMD and BMD patients because it might be a good biomarker candidate to monitor the progression of these diseases.

Highlights

Duchenne (DMD) and Becker (BMD) muscular dystrophy are X-linked muscular disorders produced by mutations in the DMD gene which encodes the protein dystrophin
There was no statistical difference in age between the DMD group and the pediatric controls (Mann-Whitney U-test, p = 0.979) and among the BMD, DYSF group and the adult control group (Kruskall-Wallis test, p = 0.052) We identified deletions in the DMD gene in 71.9% of patients
Clinical trials designed for these disorders must be able to prove presence or absence of effect in a shorter period of time

Summary

Introduction

Duchenne (DMD) and Becker (BMD) muscular dystrophy are X-linked muscular disorders produced by mutations in the DMD gene which encodes the protein dystrophin. Both diseases are characterized by progressive involvement of skeletal, cardiac, and respiratory muscles. Duchenne (DMD) and Becker (BMD) muscular dystrophy are X-linked recessive disorders produced by mutations in the DMD gene which encodes the protein dystrophin [1]. DMD has an homogeneous clinical picture characterized by early onset of muscle weakness progressing during childhood and leading to loss of ambulation during adolescence [4]. Mutations in the DMD gene lead to abnormal dystrophin expression which results in a fragile muscle membrane susceptible to be damaged during contraction [3, 6]. Continuous muscle damage leads to persistent inflammation, muscle fiber necrosis and replacement by fat and fibrous tissue, producing permanent weakness and disability [6]

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