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J. Biol. Chem., Vol. 279, Issue 16, 16332-16338, April 16, 2004

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Hypoxia Inhibits Myogenic Differentiation through Accelerated MyoD Degradation^*

Anna Di Carlo, Roberta De Mori, Fabio Martelli, Giulio Pompilio, Maurizio C. Capogrossi, and Antonia Germani¶

From the Laboratorio di Biologia Vascolare e Terapia Genica, Centro Cardiologico Monzino, Istituto di Ricovero e Cura a Carattere Scientifico, 20138 Milan, Italy, and Laboratorio di Patologia Vascolare, Istituto Dermopatico dell'Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico, 00167 Rome, Italy

Cells undergo a variety of biological responses when placed in hypoxic conditions, including alterations in metabolic state and growth rate. Here we investigated the effect of hypoxia on the ability of myogenic cells to differentiate in culture. Exposure of myoblasts to hypoxia strongly inhibited multinucleated myotube formation and the expression of differentiation markers. We showed that hypoxia reversibly inhibited MyoD, Myf5, and myogenin expression. One key step in skeletal muscle differentiation involves the up-regulation of the cell cycle-dependent kinase inhibitors p21 and p27 as well as the product of the retinoblastoma gene (pRb). Myoblasts cultured under hypoxic conditions in differentiation medium failed to up-regulate both p21 and pRb despite the G₁ cell cycle arrest, as evidenced by p27 accumulation and pRb hypophosphorylation. Hypoxia-dependent inhibition of differentiation was associated with MyoD degradation by the ubiquitin-proteasome pathway. MyoD overexpression in C2C12 myoblasts overrode the differentiation block imposed by hypoxic conditions. Thus, hypoxia by inducing MyoD degradation blocked accumulation of early myogenic differentiation markers such as myogenin and p21 and pRb, preventing both permanent cell cycle withdraw and terminal differentiation. Our study revealed a novel anti-differentiation effect exerted by hypoxia in myogenic cells and identified MyoD degradation as a relevant target of hypoxia.

Received for publication, December 19, 2003 , and in revised form, January 26, 2004.

^* 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.

^¶ To whom correspondence should be addressed: Laboratorio di Patologia Vascolare, Istituto Dermopatico dell'Immacolata-IDI, Via Monti di Creta 104, 00167 Rome, Italy. Tel.: 39-0666462428; Fax: 39-0666462430; E-mail: a.germani{at}idi.it.

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