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J. Biol. Chem., Vol. 282, Issue 43, 31453-31459, October 26, 2007

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p66^ShcA and Oxidative Stress Modulate Myogenic Differentiation and Skeletal Muscle Regeneration after Hind Limb Ischemia^*

Germana Zaccagnini¹, Fabio Martelli¹², Alessandra Magenta, Chiara Cencioni, Pasquale Fasanaro, Carmine Nicoletti^¶, Paolo Biglioli^||, Pier Giuseppe Pelicci^**, and Maurizio C. Capogrossi

From the Laboratorio di Biologia Vascolare e ^||Terapia Genica, Dipartimento di Chirurgia Vascolare, Centro Cardiologico Monzino-Instituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 20138 Milan, Italy, Laboratorio di Patologia Vascolare, Istituto Dermopatico dell'Immacolata-IRCCS, 00167 Rome, Italy, ^¶Dipartimento di Istologia ed Embriologia Medica, Università di Roma "La Sapienza", 00185 Rome, Italy, and ^**Istituto Europeo di Oncologia, 20141 Milan, Italy

Oxidative stress plays a pivotal role in ischemic injury, and p66^ShcAko mice exhibit both lower oxidative stress and decreased tissue damage following hind limb ischemia. Thus, it was investigated whether tissue regeneration following acute hind limb ischemia was altered in p66^ShcAko mice. Upon femoral artery dissection, muscle regeneration started earlier and was completed faster than in wild-type (WT) control. Moreover, faster regeneration was associated with decreased oxidative stress. Unlike ischemia, cardiotoxin injury induced similar skeletal muscle damage in both genotypes. However, p66^ShcAko mice regenerated faster, in agreement with the regenerative advantage upon ischemia. Since no difference between p66^ShcAwt and knock-out (ko) mice was found in blood perfusion recovery after ischemia, satellite cells (SCs), a resident population of myogenic progenitors, were examined. Similar SCs numbers were present in WT and ko mice. However, in vitro cultured p66^ShcAko SCs displayed lower oxidative stress levels and higher proliferation rate and differentiated faster than WT. Furthermore, when exposed to sublethal H₂O₂ doses, p66^ShcAko SCs were resistant to H₂O₂-induced inhibition of differentiation. Finally, myogenic conversion induced by MyoD overexpression was more efficient in p66^ShcAko fibroblasts compared with WT. The present work demonstrates that oxidative stress and p66^ShcA play a crucial role in the regenerative pathways activated by acute ischemia.

Received for publication, March 23, 2007 , and in revised form, August 24, 2007.

^* This work was supported in part by Ministero della Salute (RC06-1.13, RF04-Conv.102, RF05-Conv.79, and RF05-ISS 64D/F4). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S5 and supplemental references and "Materials and Methods."

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Istituto Dermopatico dell'Immacolata-IRCCS, Laboratorio Patologia Vascolare, Via dei Monti di Creta 104, 00167 Rome, Italy. Tel.: 39-06-6646-2431; Fax: 39-06-6646-2430; E-mail: f.martelli{at}idi.it.