Distinctive Serum miRNA Profile in Mouse Models of Striated Muscular Pathologies

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.

Non-coding RNAs in muscle differentiation and musculoskeletal disease

“…Moreover, such circulating miRNAs can be delivered to recipient cells, where they can control translation of target mRNAs (56,57). Specific miRNA signatures have been described in a large collection of skeletal muscle diseases (58)(59)(60)(61)(62) and neuromuscular disorders such as ALS (63). In DMD patients and mdx mice in particular, many miRNAs, including several myomiRs (miR-1, miR-133, and miR-206), are released into the blood (59,64).…”

MicroRNAs in hereditary and sporadic premature aging syndromes and other laminopathies

“…(2013) searched for miRNA deregulation in the serum of five mouse models of striated muscle pathologies: EDMD, LGMD types 2C and 2D, Duchenne muscular dystrophy, and hypertrophic cardiomyopathy. Among them, only EDMD was classified as laminopathy (mutations implicated in LGMD2C and 2D concerned gamma‐sarcoglycan gene and alpha‐sarcoglycan gene, respectively).…”

204th ENMC International Workshop on Biomarkers in Duchenne Muscular Dystrophy 24–26 January 2014, Naarden, The Netherlands

“…A collaborative study of Genethon and the Institute of Myology focused on mouse models for various muscular dystrophies. This study identified disease-specific serum miRNA profiles and the dysregulation, in common for degenerative muscular dystrophies, of the dystromiRs miR-1, miR-133a, miR-133b, miR-193b, miR-206 and miR-378 [25]. A recent multicentric large-scale study was focused on the GRMD dog model for DMD.…”