Abstract
Non-invasive biological indicators of the absence/presence or progress of the disease that could be used to support diagnosis and to evaluate the effectiveness of treatment are of utmost importance in Duchenne Muscular Dystrophy (DMD). This neuromuscular disorder affects male children, causing weakness and disability, whereas female relatives are at risk of being carriers of the disease. A biomarker with both high sensitivity and specificity for accurate prediction is preferred. Until now creatine kinase (CK) levels have been used for DMD diagnosis but these fail to assess disease progression. Herein we examined the potential applicability of serum levels of matrix metalloproteinase 9 (MMP-9) and matrix metalloproteinase 2 (MMP-2), tissue inhibitor of metalloproteinases 1 (TIMP-1), myostatin (GDF-8) and follistatin (FSTN) as non-invasive biomarkers to distinguish between DMD steroid naïve patients and healthy controls of similar age and also for carrier detection. Our data suggest that serum levels of MMP-9, GDF-8 and FSTN are useful to discriminate DMD from controls (p < 0.05), to correlate with some neuromuscular assessments for DMD, and also to differentiate between Becker muscular dystrophy (BMD) and Limb-girdle muscular dystrophy (LGMD) patients. In DMD individuals under steroid treatment, GDF-8 levels increased as FSTN levels decreased, resembling the proportions of these proteins in healthy controls and also the baseline ratio of patients without steroids. GDF-8 and FSTN serum levels were also useful for carrier detection (p < 0.05). Longitudinal studies with larger cohorts are necessary to confirm that these molecules correlate with disease progression. The biomarkers presented herein could potentially outperform CK levels for carrier detection and also harbor potential for monitoring disease progression.
Highlights
Skeletal muscle tissue provides mechanical strength, confers the ability to move and behaves as a large repository of building blocks for protein synthesis in living beings [1]
matrix metalloproteinase 9 (MMP-9) may be predominantly involved in the inflammatory course during muscle degeneration, whereas matrix metalloproteinase 2 (MMP-2) is activated in regenerating fibers associated with extracellular matrix (ECM)
Unlike the report by Nadarajah and colleagues that included patients under steroid treatment [6], in the present study, serum levels of matrix metalloproteinases (MMPs)-9, MMP-2 and tissue inhibitor of metalloproteinases 1 (TIMP-1) were analyzed in a Duchenne Muscular Dystrophy (DMD) group of steroid naïve ambulant patients (n = 19, age = range 3–12; mean and SD = 8.2 ± 2.1 years) and in a control group of healthy male children (n = 21, age = range 5–13; mean and SD 9.9 ± 2.5 years)
Summary
Skeletal muscle tissue provides mechanical strength, confers the ability to move and behaves as a large repository of building blocks for protein synthesis in living beings [1]. When functional dystrophin is lacking muscles are more sensitive to movement-induced damage, leading to membrane fragility, abnormal calcium influx and activation of proteolytic enzymes; leading to extracellular matrix (ECM) breakdown, necrosis, chronic inflammation and replacement of muscle by endomysial fibrosis and adipose tissue deposits [6]. Several inflammatory molecules and regulators of ECM are disrupted in muscle biopsies from DMD patients and in skeletal muscle of animal DMD models. Among these molecules we can find matrix metalloproteinases (MMPs), which are zinc-containing and calcium-dependent proteases involved in ECM remodeling, inflammation, fibrosis, and activation of various latent cytokines [7,8].
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