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J. Biol. Chem., Vol. 281, Issue 51, 39672-39680, December 22, 2006

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A Mouse Model for Monitoring Calpain Activity under Physiological and Pathological Conditions^*

Marc Bartoli¹, Nathalie Bourg¹, Daniel Stockholm¹, Fabrice Raynaud, Antony Delevacque, Yang Han, Perrine Borel, Kenza Seddik, Nasser Armande, and Isabelle Richard²

From the Généthon/CNRS-UMR8115, 1 rue de l'Internationale 91000 Evry, France and CNRS-UMR5539/Université de Montpellier, Place E. Bataillon, 34000 Montpellier, France

Calpains are Ca²⁺-dependent cysteine proteases known to be important for the regulation of cell functions and which aberrant activation causes cell death in a number of degenerative disorders. To provide a tool for monitoring the status of calpain activity in vivo under physiological and pathological conditions, we created a mouse model that expresses ubiquitously a fluorescent reporter consisting of eCFP and eYFP separated by a linker cleavable by the ubiquitous calpains. We named this mouse CAFI for calpain activity monitored by FRET imaging. Our validation studies demonstrated that the level of calpain activity correlates with a decrease in FRET (fluorescence resonance energy transfer) between the two fluorescent proteins. Using this model, we observed a small level of activity after denervation and fasting, a high level of activity during muscle regeneration and ischemia, and local activity in damaged myofibers after exercise. Finally, we crossed the CAFI mouse with the -sarcoglycan-deficient model, demonstrating an increase of calpain activity at the steady state. Altogether, our results present evidence that CAFI mice could be a valuable tool in which to follow calpain activity at physiological levels and in disease states.

Received for publication, September 12, 2006

^* This work was funded in part by the Association Française contre les Myopathies, Genopole® (Evry) and the Fondation pour la Recherche Médicale. 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.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Généthon/CNRS-UMR8115, 1 rue de l'Internationale, 91000 Evry, France. Tel.: 33-1-69-47-29-38; Fax: 33-1-60-77-86-98; E-mail: richard{at}genethon.fr.

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