Distinctive patterns of microRNA expression in primary muscular disorders

doi:10.1073/pnas.0708115104

Distinctive patterns of microRNA expression in primary muscular disorders

^aHoward Hughes Medical Institute,
^bProgram in Genomics, Division of Genetics,
^cInformatics Program, and
Departments of ^gPathology and
^hNeurology, Children's Hospital, Harvard Medical School, Boston, MA 02115;
^dDepartment of Neuromuscular Research, National Institute of Neuroscience, Tokyo 187-8502, Japan;
^eDepartment of Neurology, University of Milan, 20122 Milan, Italy;
^fDepartment of Neurology, Brigham and Women's Hospital, Boston, MA 02115;
ⁱInstitute for Neuromuscular Research, The Children's Hospital at Westmead, New South Wales 2145, Australia;
^jGoldyne Savad Institute of Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem 91240, Israel;
^kDepartment of Human Genetics, University of Utah, Salt Lake City, UT 84132; and
^lUS Genomics, Woburn, MA 01801

Contributed by Louis M. Kunkel, August 30, 2007 (received for review July 25, 2007)

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.

Footnotes

^mTo whom correspondence should be addressed. E-mail: kunkel{at}enders.tch.harvard.edu
Author contributions: I.E. and L.M.K. designed research; I.E. and L.A.N. performed research; I.N., M.M., C.L., A.A.A., H.G.L., P.B.K., K.N.N., S.M.-R., K.M.F., and A.H.B. contributed new reagents/analytic tools; I.E., A.E., L.A.N., D.W., and I.S.K. analyzed data; and I.E. and L.M.K. wrote the paper;
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0708115104/DC1.
Abbreviations:

miRNA,

microRNA;

DMD,

Duchenne muscular dystrophy;

BMD,

Becker muscular dystrophy;

FSHD,

facioscapulohumeral muscular dystrophy;

LGMD,

limb-girdle muscular dystrophies;

LGMD2A,

LGMD type 2A;

LGMD2B,

LGMD type 2B;

NM,

nemaline myopathy;

MM,

Miyoshi myopathy;

IBM,

inclusion body myositis;

DM,

dermatomyositis;

PM,

polymyositis;

PCA,

principal component analysis;

ECM,

extracellular matrix.
Freely available online through the PNAS open access option.