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Common micro-RNA signature in skeletal muscle damage and regeneration induced by Duchenne muscular dystrophy and acute ischemia

Simona Greco^*,1, Marco De Simone^,1, Claudia Colussi, Germana Zaccagnini, Pasquale Fasanaro, Mario Pescatori^||, Rosanna Cardani^¶, Riccardo Perbellini^*,¶, Eleonora Isaia^*, Patrizio Sale, Giovanni Meola^*,¶, Maurizio C. Capogrossi, Carlo Gaetano and Fabio Martelli^,2

^* Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Donato, San Donato Milanese, Milan, Italy;

Centro Cardiologico Monzino—IRCCS, Milan, Italy;

Istituto Dermopatico dell'Immacolata—IRCCS and

San Raffaele Pisana—IRCCS, Rome, Italy;

^|| Erasmus Medical Center, Rotterdam, The Netherlands; and

^¶ Università di Milano, Milan, Italy

² Correspondence: Laboratorio Patologia Vascolare, Istituto Dermopatico dell'Immacolata—IRCCS, Rome, Italy. E-mail: f.martelli{at}idi.it

The aim of this work was to identify micro-RNAs (miRNAs) involved in the pathological pathways activated in skeletal muscle damage and regeneration by both dystrophin absence and acute ischemia. Eleven miRNAs were deregulated both in MDX mice and in Duchenne muscular dystrophy patients (DMD signature). Therapeutic interventions ameliorating the mdx-phenotype rescued DMD-signature alterations. The significance of DMD-signature changes was characterized using a damage/regeneration mouse model of hind-limb ischemia and newborn mice. According to their expression, DMD-signature miRNAs were divided into 3 classes. 1) Regeneration miRNAs, miR-31, miR-34c, miR-206, miR-335, miR-449, and miR-494, which were induced in MDX mice and in DMD patients, but also in newborn mice and in newly formed myofibers during postischemic regeneration. Notably, miR-206, miR-34c, and miR-335 were up-regulated following myoblast differentiation in vitro. 2) Degenerative-miRNAs, miR-1, miR-29c, and miR-135a, that were down-modulated in MDX mice, in DMD patients, in the degenerative phase of the ischemia response, and in newborn mice. Their down-modulation was linked to myofiber loss and fibrosis. 3) Inflammatory miRNAs, miR-222 and miR-223, which were expressed in damaged muscle areas, and their expression correlated with the presence of infiltrating inflammatory cells. These findings show an important role of miRNAs in physiopathological pathways regulating muscle response to damage and regeneration.—Greco, S., De Simone, M., Colussi, C., Zaccagnini, G., Fasanaro, P., Pescatori, M., Cardani, R., Perbellini, R., Isaia, E., Sale, P., Meola, G., Capogrossi, M. C., Gaetano, C., Martelli, F. Common micro-RNA signature in skeletal muscle damage and regeneration induced by Duchenne muscular dystrophy and acute ischemia.

Key Words: tissue degeneration • inflammation • myogenic differentiation • therapy