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This Article Accepted manuscript (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.

D Brown, Medicine, Charles Drew university, Los Angeles, United States
A Sina-Hikim, Endocrinology, LABiomed Harbor UCLA David Geffen School of Medicine, Torrance, United States
E Kovacheva, Medicine, Charles Drew university, Los Angeles, United States
I Sinha-Hikim, Medicine, Div: Endocrinology, Charles Drew University, Los Angeles, 90059, United States

Correspondence: Indrani Sinha-Hikim, Email: insinhah{at}cdrewu.edu

Abstract

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.

Adult mice (C57BL/6) received one of the following treatments: 1) vehicle (sterile distilled water; normal control) and 2) gonadotropin-releasing hormone antagonist (GnRH-A) with empty (sham control) or 2 cm T- filled implant. Mice were killed 2, 6, and 8 wk after treatment. T treatment for 8 wk 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. We also observed an increase in the number of PCNA-positive nuclei in muscles of T-treated mice, indicating that activation of Notch signaling enhanced cell proliferation. T supplementation not only triggered p38 MAPK activation but also concurrently inhibited c-Jun NH2-terminal kinase (JNK) activation with 2 wk 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.