title: MicroRNA expression profiling in patients with lamin A/C-associated muscular dystrophy.
abstract: Mutations in the lamin A/C gene (LMNA) cause several disorders referred to as laminopathies, which include premature aging syndromes, lipodystrophy, and striated muscle disorders. There is evidence that lamin A/C plays a role in gene expression. MicroRNAs (miRNAs) are short noncoding RNAs regulating mRNAs involved in various biological processes, including the pathophysiology of striated muscles. Here, we profiled the expression of the miRNA transcriptome in skeletal muscle from patients with LMNA-related muscular dystrophy. Results show that control and patient groups can be distinguished based on their miRNA expression profile. Sixteen miRNAs are significantly dysregulated in patients compared with controls. Pathway enrichment analysis in the predicted targets of these miRNAs revealed pathways involved in muscle repair, such as MAPK, transforming growth factor-β, and Wnt signaling. Interestingly, 9 of these miRNAs (hsa-miR-100, -127-3p, -148a, -136*, -192, -335, -376c, -489, and -502-3p) are highly expressed in fetal muscle, suggesting that the fetal miRNA gene program mediates a regenerative process. Overexpression of these miRNAs in C2C12 mouse myoblasts revealed that 3 of them (miR-100, -192, and -335) participate in muscle proliferation and differentiation. We identified target genes that likely mediate this effect, which include the calcineurin gene PPP3CA. Our findings are the first to demonstrate that miRNA expression is affected in laminopathies.
authors.affiliation: Department of Biochemistry, University of Leicester, Leicester, UK. ns249@le.ac.uk
authors.forename: Nicolas
authors.initials: N
authors.lastname: Sylvius
authors.forename: Gisèle
authors.initials: G
authors.lastname: Bonne
authors.forename: Kees
authors.initials: K
authors.lastname: Straatman
authors.forename: Thimma
authors.initials: T
authors.lastname: Reddy
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Gant
authors.forename: Sue
authors.initials: S
authors.lastname: Shackleton
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D015870:Gene Expression; D006801:Humans; D034904:Lamin Type A / Q000235:genetics*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism; D009136:Muscular Dystrophies / Q000235:genetics* / Q000473:pathology; D015854:Up-Regulation
chemical_list: D034904:Lamin Type A; C544266:MIRN100 microRNA, human; C546783:MIRN192 microRNA, human; C556347:MIRN335 microRNA, human; D035683:MicroRNAs; C440308:lamin C