Hmgb3 is regulated by microRNA-206 during muscle regeneration.
BACKGROUND
MicroRNAs (miRNAs) have been recently involved in most of human diseases as targets for potential strategies to rescue the pathological phenotype. Since the skeletal muscle is a spread-wide highly differentiated and organized tissue, rescue of severely compromised muscle still remains distant from nowadays. For this reason, we aimed to identify a subset of miRNAs major involved in muscle remodelling and regeneration by analysing the miRNA-profile of single fibres isolated from dystrophic muscle, which was here considered as a model of chronic damage.


RESULTS
The miRNA-signature associated to regenerating (newly formed) and remodelling (resting) fibres was investigated in animal models of muscular dystrophies and acute damage, in order to distinguish which miRNAs are primary related to muscle regeneration. In this study we identify fourteen miRNAs associated to dystrophic fibres responsible for muscle regeneration and remodelling, and confirm over-expression of the previously identified regeneration-associated myomiR-206. In particular, a functional binding site for myomiR-206 was identified and validated in the 3'untranslated region (3'UTR) of an X-linked member of a family of sequence independent chromatin-binding proteins (Hmgb3) that is preferentially expressed in hematopoietic stem cells. During regeneration of single muscle fibres, Hmgb3 messenger RNA (mRNA) and protein expression was gradually reduced, concurrent with the up-regulation of miR-206.


CONCLUSIONS
Our results elucidate a negative feedback circuit in which myomiR-206 represses Hmgb3 expression to modulate the regeneration of single muscle fibres after acute and chronic muscle damage. These findings suggest that myomiR-206 may be a potential therapeutic target in muscle diseases.
Stem Cell Laboratory, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Centro Dino Ferrari, Milano, Italy.
Simona
S
Maciotta
Mirella
M
Meregalli
Letizia
L
Cassinelli
Daniele
D
Parolini
Andrea
A
Farini
Giulia Del
GD
Fraro
Francesco
F
Gandolfi
Mattia
M
Forcato
Sergio
S
Ferrari
Davide
D
Gabellini
Silvio
S
Bicciato
Giulio
G
Cossu
Yvan
Y
Torrente
D020413:3' Untranslated Regions / Q000235:genetics; D000293:Adolescent; D000818:Animals; D000831:Animals, Newborn; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D002648:Child; D002675:Child, Preschool; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D025765:HMGB3 Protein / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009136:Muscular Dystrophies / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D009137:Muscular Dystrophy, Animal / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D041681:NIH 3T3 Cells; D020411:Oligonucleotide Array Sequence Analysis; D012038:Regeneration / Q000235:genetics*
D020413:3' Untranslated Regions; D025765:HMGB3 Protein; C546087:MIRN206 microRNA, human; D035683:MicroRNAs; C540669:Mirn206 microRNA, mouse