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This Article Full Text Full Text (PDF) All Versions of this Article: JOE-08-0476v1 201/1/129    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Brown, D. Articles by Sinha-Hikim, I. Search for Related Content PubMed PubMed Citation Articles by Brown, D. Articles by Sinha-Hikim, I.

Division of Endocrinology, Charles Drew University, Los Angeles, California 90059, USA¹ Division of Endocrinology, David Geffen School of Medicine at UCLA and Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, California 90509, USA

(Correspondence should be addressed to I Sinha-Hikim who is now at Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R Drew University, Los Angeles, California 90059, USA; Email: insinhah{at}cdrewu.edu)

As a prerequisite for studies using mutant mice, we established a mouse model for investigating the molecular mechanisms by which testosterone (T) promotes muscle growth. Groups of six adult male mice (C57BL/6) received one of the following treatments: 1) vehicle (sterile distilled water; normal control) and 2) GnRH antagonist with empty (sham control) or 2 cm T- filled implant. Mice were killed 2, 6, and 8 weeks after treatment. T treatment for 8 weeks resulted in a significant (P<0.001) increase in fiber area of gastrocnemius muscles. T-induced fiber-hypertrophy was accompanied by up-regulation of the Notch ligand Delta 1 and activation of Notch signaling, as evidenced by increase in activated forms of Notch 1 and Notch 2. Consistent with this, we also observed an increase in the number of proliferating cell nuclear antigen (PCNA)-positive nuclei in muscles of T-treated mice, indicating that activation of Notch signaling enhanced cell proliferation. T supplementation not only triggered p38 mitogen-activated protein kinase (MAPK) activation but also concurrently inhibited c-Jun NH₂-terminal kinase (JNK) activation within 2 weeks of treatment. Concomitant administration of SB203580, a p38 MAPK inhibitor, effectively blocked T-induced activation of Notch signaling and significantly (P<0.001) suppressed PCNA levels. Together, our results indicate that T induces muscle fiber hypertrophy through activation of Notch signaling and the inactivation of JNK together with the activation of p38 MAPK may be critical for T-induced activation of Notch signaling and, as a consequence, muscle fiber hypertrophy.