Abstract
Biomarkers are critically important for disease diagnosis and monitoring. In particular, close monitoring of disease evolution is eminently required for the evaluation of therapeutic treatments. Classical monitoring methods in muscular dystrophies are largely based on histological and molecular analyses of muscle biopsies. Such biopsies are invasive and therefore difficult to obtain. The serum protein creatine kinase is a useful biomarker, which is however not specific for a given pathology and correlates poorly with the severity or course of the muscular pathology. The aim of the present study was the systematic evaluation of serum microRNAs (miRNAs) as biomarkers in striated muscle pathologies. Mouse models for five striated muscle pathologies were investigated: Duchenne muscular dystrophy (DMD), limb-girdle muscular dystrophy type 2D (LGMD2D), limb-girdle muscular dystrophy type 2C (LGMD2C), Emery-Dreifuss muscular dystrophy (EDMD) and hypertrophic cardiomyopathy (HCM). Two-step RT-qPCR methodology was elaborated, using two different RT-qPCR miRNA quantification technologies. We identified miRNA modulation in the serum of all the five mouse models. The most highly dysregulated serum miRNAs were found to be commonly upregulated in DMD, LGMD2D and LGMD2C mouse models, which all exhibit massive destruction of striated muscle tissues. Some of these miRNAs were down rather than upregulated in the EDMD mice, a model without massive myofiber destruction. The dysregulated miRNAs identified in the HCM model were different, with the exception of one dysregulated miRNA common to all pathologies. Importantly, a specific and distinctive circulating miRNA profile was identified for each studied pathological mouse model. The differential expression of a few dysregulated miRNAs in the DMD mice was further evaluated in DMD patients, providing new candidates of circulating miRNA biomarkers for DMD.
Highlights
Muscular dystrophies are a large heterogeneous group of over 30 different inherited disorders characterized by muscle wasting and weakness of variable distribution and severity, with or without heart defects, manifesting at any age from birth to senescence, and resulting in significant morbidity and disability [1]
Experimental Design As we aimed to identify circulating miRNA biomarker profile of different muscular pathologies, we have selected 5 mouse models of skeletal and/or cardiac muscle diseases that involved different pathophysiological pathways and different degree of impairment of either tissue
Sgca-null mice were used as models for limb-girdle muscular dystrophy type 2D (LGMD2D) [24], Sgcg-null mice for limb-girdle muscular dystrophy type 2C (LGMD2C) [25], mdx-4CV mice for Duchenne muscular dystrophy (DMD) [26]
Summary
Muscular dystrophies are a large heterogeneous group of over 30 different inherited disorders characterized by muscle wasting and weakness of variable distribution and severity, with or without heart defects, manifesting at any age from birth to senescence, and resulting in significant morbidity and disability [1]. The diseases are defined and classified according to their genetic cause as well as clinical and pathological manifestation, the distribution of predominant muscle weakness and the presence or not of other organ involvement. Cardiomyopathies occur without skeletal muscle involvement and present a wide clinical and genetic heterogeneity [3]. The principal analytical methods for muscular dystrophies diagnosis are based on muscle biopsy immunohistochemistry and Western blot analyses, serum content of muscle creatine kinase (CK), electromyography, electrocardiography and DNA mutation analysis [1]. As for early cardiac disease diagnosis, serum markers such as NT-ProBNP might be reliable for early detection of myocardial dysfunction, and lack specificity [5]
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call