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This Article Free via Open Access: OA OA Full Text Full Text (PDF) Supplemental Data OA All Versions of this Article: 2007-0493v1 26/4/997    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Google Scholar Articles by Moresi, V. Articles by Coletti, D. PubMed PubMed Citation Articles by Moresi, V. Articles by Coletti, D.

TISSUE-SPECIFIC STEM CELLS

Tumor Necrosis Factor- Inhibition of Skeletal Muscle Regeneration Is Mediated by a Caspase-Dependent Stem Cell Response

^aDepartment of Histology and Medical Embryology and
^bInteruniversity Institute of Myology, Sapienza University, Rome, Italy;
^cBiotechmed, ENEA-Casaccia, Rome, Italy;
^dMyology Group INSERM U787, Université Pierre et Marie Curie, Paris, France

Key Words. Peg3/PW1 • Adult stem cells • Muscle stem cells • Cytokines • Caspase assay • Gene delivery by electroporation

Correspondence: Sergio Adamo, M.D., Department of Histology and Medical Embryology, Via A. Scarpa 14, 00161 Rome, Italy. Telephone: 39-0649766756; Fax: 39-0649766643; e-mail: sergio.adamo{at}uniroma1.it

Received June 21, 2007; accepted for publication January 15, 2008.
First published online in STEM CELLS EXPRESS   February 7, 2008.



Skeletal muscle is susceptible to injury following trauma, neurological dysfunction, and genetic diseases. Skeletal muscle homeostasis is maintained by a pronounced regenerative capacity, which includes the recruitment of stem cells. Chronic exposure to tumor necrosis factor- (TNF) triggers a muscle wasting reminiscent of cachexia. To better understand the effects of TNF upon muscle homeostasis and stem cells, we exposed injured muscle to TNF at specific time points during regeneration. TNF exposure delayed the appearance of regenerating fibers, without exacerbating fiber death following the initial trauma. We observed modest cellular caspase activation during regeneration, which was markedly increased in response to TNF exposure concomitant with an inhibition in regeneration. Caspase activation did not lead to apoptosis and did not involve caspase-3. Inhibition of caspase activity improved muscle regeneration in either the absence or the presence of TNF, revealing a nonapoptotic role for this pathway in the myogenic program. Caspase activity was localized to the interstitial cells, which also express Sca-1, CD34, and PW1. Perturbation of PW1 activity blocked caspase activation and improved regeneration. The restricted localization of Sca-1⁺, CD34⁺, PW1⁺ cells to a subset of interstitial cells with caspase activity reveals a critical regulatory role for this population during myogenesis, which may directly contribute to resident muscle stem cells or indirectly regulate stem cells through cell-cell interactions.

Disclosure of potential conflicts of interest is found at the end of this article.