Cytokines as Potential Biomarkers of Disease Clinical Course in Muscular Dystrophies

*Luisa Politano
Cardio Myology And Medical Genetics, Luigi Vanvitelli University, 80138 Naples, Italy

*Corresponding Author:
Luisa Politano
Cardio Myology And Medical Genetics, Luigi Vanvitelli University, 80138 Naples, Italy
Email:poli3295@gmail.com

Published on: 2021-05-31

Abstract

Background: Muscular dystrophies (MDs) are rare neuromuscular disorders characterized by phenotypic variability and frequent cardiac involvement. MDs genotype-phenotype correlations are challenging due to the clinical variability and disease rarity and clinical, and nonclinical factors predicting myopathy progression and heart involvement are substantially lacking.
Aim: Finding serum biomarkers identifying myopathy and early cardiomyopathy.
Methods: Serum levels of 17 pro-and anti-inflammatory molecules, including cytokines, chemokines and growth factors, were quantified in 17 MDs patients with Emery Dreifuss Muscular Dystrophy (EDMD1), Duchenne and Becker muscular dystrophy (DMD/BMD), Myotonic Dystrophy type 1 (DM1), and in 22 age-matched healthy individuals.
Results: IL-17, GM-CSF and MCP-1 on one side and IL-13 and MIP-1a on the other side, discriminated among MDs patients, those with and without cardiac involvement compared with healthy subjects.
Conclusion: These findings suggest that monitoring of specific cytokines may be useful for early identification of cardiomyopathy in MD allowing earlier appropriate treatments.

Keywords

Cytokines; Muscular Dystrophies; Muscle damage; Myocardial damage; Biomarkers

Introduction

Muscular dystrophies (MDs) represent a complex, varied, and important subset of neuromuscular disorders ranging from severe and fatal congenital muscular dystrophies with onset in infancy to mild forms of limb and girdle weakness with onset in adolescence or adulthood [1]. Cardiac involvement is a frequent feature in this group of diseases, presenting as both systolic dysfunction, evolving to dilated cardiomyopathy (DCM) and heart failure (HF), and conduction system abnormalities [2].
There is an emerging interest and need for nonclinical biomarkers in assessing the clinical course and diagnosing MDs, as well as in monitoring drug therapy [3-5]. However, the problem is not so much finding potential candidates as their validation and translation into clinical practice. This difficulty is even more evident in MDs due to their phenotypic variability, but above all because of their rarity, which prevents assembling a large cohort of patients.
Cytokines are mediators of inflammation released by a variety of cell types and regulate a wide variety of metabolic, inflammatory, and regenerative processes [6,7]. The abnormal increase in the level of proinflammatory molecules such as TNF-α and IL-1 β has been suggested as being among the major mechanisms triggering muscle wasting [6,7]. Increasing evidence indicates that the inflammatory processes are highly integrated into muscle wasting in DMD and that circulating inflammatory cytokines maybe 1000 times higher in DMD human patients than healthy controls [6-8]. It is also known that oxidative stress and chronic inflammation are involved in the physiopathology of MDs. Disruption of the dystroglycan complex leads to high susceptibility to injury, with repeated, eccentric contractions as well as inflammation, resulting in significant damage and necrosis. Chronic damage and repair cycling leads to fibrosis and weakness [9].
Several trials demonstrated that the process of inflammation might be responsible for the initiation of DCM and progression to HF [10- 11]. In HF there is an activation of the immune system, production, and release of autoantibodies, pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), and complement system recruitment [10-11]. High levels of circulating cytokines correlate with the severity of HF measured with the use of the New York Heart Association (NYHA) classification, and prognosis of the disease [10-13]. They also cause alterations in the heart function due to the increase of cardiomyocyte apoptosis, cardiac hypertrophy, and matrix metalloproteinase activation [10]. Cytokines levels in serum of 24 Muscular Dystrophy patients, DMD (n=7), DM1 (n=10), and LGMD2A (n=7) were evaluated by Comim CM, et al. (2019) They found an increase of IL-1β in DMD and DM1 patients, while TNF-α was increased only in DMD patients, and IL-10 decreased in all the analyzed groups. They suggested that in muscular dystrophies there could be a pro-inflammatory state due to the disease itself and an anti-inflammatory counterpart trying to balance the generated inflammation and perhaps restrain the progressive characteristic of the disease [14].
Cappelletti C, et al. (2020) [15] investigated the serum levels of 51 pro-and anti-inflammatory molecules, including cytokines, chemokines, and growth factors, in 85 patients with different types of MDs and 35 healthy controls. They showed that a) the levels of interleukin-17 (IL-17), granulocyte colony-stimulating factor (G-CSF), and transforming growth factor-beta (TGF-β2) significantly discriminated patients affected by muscular Laminopathies (Musc- LMNA) from controls; b) interleukin-1β (IL-1β), interleukin-4 (IL-4) and interleukin-8 (IL-8) were differentially expressed in Musc-LMNA patients compared to those with non-muscular laminopathies; c) IL- 17 was significantly higher in Musc-LMNA patients who presented cardiac involvement.
In this preliminary communication, we analyzed the cytokine profile in patients with X-linked Emery Dreifuss Muscular Dystrophy (EDMD1), Duchenne and Becker muscular dystrophies, (DMD/ BMD), and Myotonic Dystrophy type 1 (DM1) to determine whether an abnormal profile of circulating cytokines could be identified, helping to distinguish the different MDs, and, within the same disease, identify early onset of cardiac involvement.

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