Distinctive patterns of microRNA expression in primary muscular disorders

Abstract

The primary muscle disorders are a diverse group of diseases caused by various defective structural proteins, abnormal signaling molecules, enzymes and proteins involved in posttranslational modifications, and other mechanisms. Although there is increasing clarification of the primary aberrant cellular processes responsible for these conditions, the decisive factors involved in the secondary pathogenic cascades are still mainly obscure. Given the emerging roles of microRNAs (miRNAs) in modulation of cellular phenotypes, we searched for miRNAs regulated during the degenerative process of muscle to gain insight into the specific regulation of genes that are disrupted in pathological muscle conditions. We describe 185 miRNAs that are up- or down-regulated in 10 major muscular disorders in humans [Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, facioscapulohumeral muscular dystrophy, limb-girdle muscular dystrophies types 2A and 2B, Miyoshi myopathy, nemaline myopathy, polymyositis, dermatomyositis, and inclusion body myositis]. Although five miRNAs were found to be consistently regulated in almost all samples analyzed, pointing to possible involvement of a common regulatory mechanism, others were dysregulated only in one disease and not at all in the other disorders. Functional correlation between the predicted targets of these miRNAs and mRNA expression demonstrated tight posttranscriptional regulation at the mRNA level in DMD and Miyoshi myopathy. Together with direct mRNA–miRNA predicted interactions demonstrated in DMD, some of which are involved in known secondary response functions and others that are involved in muscle regeneration, these findings suggest an important role of miRNAs in specific physiological pathways underlying the disease pathology.

MicroRNA-199a is induced in dystrophic muscle and affects WNT signaling, cell proliferation, and myogenic differentiation

“…Thus, we chose to utilize the sapje dystrophic zebrafish as a model for analyzing dysregulated dystrophic miRNAs and to expand our previous findings obtained from DMD muscle biopsies. 12 Here we have identified miRNAs that are commonly dysregulated in both zebrafish and human muscle DMD biopsies. One of these dysregulated miRNAs, miR-199a-5p, was conservatively induced in expression in dystrophic zebrafish, mouse, and human muscle.…”

“…9 MicroRNAs (miRNAs) have been shown to have an essential role in muscle development, differentiation, and disease. [10][11][12][13][14][15] Previously, we defined a miRNA biosignature of different muscle diseases and revealed dysregulated miRNAs that were either common or unique to each muscle disease. 12 Additional studies using the dystrophic mdx mouse muscle identified dysregulated miRNAs as a result of nNOS destabilization from the muscle membrane.…”

“…[10][11][12][13][14][15] Previously, we defined a miRNA biosignature of different muscle diseases and revealed dysregulated miRNAs that were either common or unique to each muscle disease. 12 Additional studies using the dystrophic mdx mouse muscle identified dysregulated miRNAs as a result of nNOS destabilization from the muscle membrane. 11 Nevertheless, studies in the mdx dystrophic mouse model have limitations in their clinical usefulness due to the lack of severity of the disease progression in the mouse muscles.…”

“…Previous studies have shown that miR-199a transcript is increased in expression in both human DMD muscle biopsies and the quadriceps and diaphragm muscles of mdx mice. 12,19 Overexpression or knockdown of miR-199a-5p in primary human myoblasts (MB) resulted in dramatic changes in cell size, differentiation, and proliferative capacity. Manipulation of miR-199a-5p levels in primary human MB and myotubes (MT) results in dramatic changes in myogenic cell proliferation, shape, and differentiation.…”

MicroRNAs in hereditary and sporadic premature aging syndromes and other laminopathies

“…The unsupervised hierarchical clustering of these miRNAs allowed the separation between normal and LMNA mutated biopsies and identified a miRNA signature. Sixteen miRNAs were upregulated in patients, including eight already described in other studies as upregulated in other muscle or cardiac disorders (Eisenberg et al., 2007; e.g., Duchenne muscular dystrophy and limb‐girdle muscular dystrophy types 2A and 2B). The authors focused their attention on miR‐100, miR‐192, and miR‐335, which were also found to be highly expressed in fetal skeletal muscle.…”