Abstract 10655: Fundamental Role for Class IIa Histone Deacetylases in the Regulation of Myo-miRs Expression Following Hind-Limb Ischemia and Muscle Regeneration
INTRODUCTION: NO is a potent regulator of epigenetic processes including class I histone deacetylases (HDAC) nitrosylation and inactivation and class IIa nuclear translocation and activation. Although class IIa regulates important biological processes little is known about its role during muscle regeneration and following acute hindlimb ischemia.
METHODS & RESULTS: hindlimb ischemia was generated in C57BL10-J6 mice (n=12) by surgical excision of femoral artery and collaterals ligation. Sham operated mice were used as controls (n=12). Animals were sacrificed at 3, 7, 14 and 21 days after surgery and adductor muscles taken for functional and histological evaluation. Additional animals were made ischemic or sham operated and treated with the selective class IIa inhibitor MC1568 (40 mg/Kg/day; n=12) or an equivalent amount of solvent (DMSO; n=12). Histological analyses revealed that, in early regenerating muscle fibres (3 days), class IIa HDAC 4 and 5 were mostly localized outside the nucleus, becaming nuclear at the later time-points of 14 and 21days. The in vivo evaluation of class IIa activity revealed a progressive increase of class IIa function detectable in the nuclear fraction of regenerating adductor fibres which paralleled the HDAC 4 and 5 nuclear localization. Remarkably, in the presence of MC1568, post-ischemia muscle regeneration was significantly delayed and large inflammation/infiltration areas were still detectable at the 14 days time-point where mature muscular fibres were virtually absent. Strong histone H3 acetylation and phosphorylation signal were also present and paralleled by reduced levels of myo-miRs including miR-1, -34c, -222, -223, -335, -494.
CONCLUSION: Taken altogether these findings indicate that class IIa localization and activation is important during muscle regeneration after hindlimb ischemia providing an unprecedented functional link between HDAC function and myo-miRs expression.
- © 2011 by American Heart Association, Inc.