Heme oxygenase-1 inhibits myoblast differentiation by targeting myomirs.


AIMS Heme oxygenase-1 (HMOX1) is a cytoprotective enzyme degrading heme to biliverdin, iron ions, and carbon monoxide, whose expression is induced in response to oxidative stress. Its overexpression has been suggested as a strategy improving survival of transplanted muscle precursors. RESULTS Here we demonstrated that HMOX1 inhibits differentiation of myoblasts and modulates miRNA processing: downregulates Lin28 and DGCR8, lowers the total pool of cellular miRNAs, and specifically blocks induction of myomirs. Genetic or pharmacological activation of HMOX1 in C2C12 cells reduces the abundance of miR-1, miR-133a, miR-133b, and miR-206, which is accompanied by augmented production of SDF-1 and miR-146a, decreased expression of MyoD, myogenin, and myosin, and disturbed formation of myotubes. Similar relationships between HMOX1 and myomirs were demonstrated in murine primary satellite cells isolated from skeletal muscles of HMOX1(+/+), HMOX1(+/-), and HMOX1(-/-) mice or in human rhabdomyosarcoma cell lines. Inhibition of myogenic development is independent of antioxidative properties of HMOX1. Instead it is mediated by CO-dependent inhibition of c/EBPδ binding to myoD promoter, can be imitated by SDF-1, and partially reversed by enforced expression of miR-133b and miR-206. Control C2C12 myoblasts injected to gastrocnemius muscles of NOD-SCID mice contribute to formation of muscle fibers. In contrast, HMOX1 overexpressing C2C12 myoblasts form fast growing, hyperplastic tumors, infiltrating the surrounding tissues, and disseminating to the lungs. INNOVATION We evidenced for the first time that HMOX1 inhibits differentiation of myoblasts, affects the miRNA processing enzymes, and modulates the miRNA transcriptome. CONCLUSION HMOX1 improves the survival of myoblasts, but concurrently through regulation of myomirs, may act similarly to oncogenes, increasing the risk of hyperplastic growth of myogenic precursors.

DOI: 10.1089/ars.2011.3964
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@article{Kozakowska2012HemeOI, title={Heme oxygenase-1 inhibits myoblast differentiation by targeting myomirs.}, author={Magdalena Kozakowska and Maciej Cieśla and Anna Stefanska and Klaudia Skrzypek and Halina Waś and Agnieszka Jaźwa and Anna Grochot-Przęczek and Jerzy Kotlinowski and Agnieszka Szymula and Aleksandra Bartelik and Milena Mazan and Oleksandr Yagensky and Urszula M. Florczyk and Krzysztof Lemke and Anna Zebzda and Grzegorz Dyduch and Witold Norbert Nowak and Krzysztof Tomasz Szade and Jacek Stępniewski and Marcin Majka and Rafal Derlacz and Agnieszka Loboda and J{\'o}zef Dulak and Alicja Jozkowicz}, journal={Antioxidants & redox signaling}, year={2012}, volume={16 2}, pages={113-27} }