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Nerve‐derived agrin cooperates with neural activity to potentiate translational control of skeletal muscle growth via p70 S6K
Author(s) -
Michel Robin Nicholas,
Kulig Ewa M.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.959.24
Subject(s) - p70 s6 kinase 1 , agrin , phosphorylation , neuroscience , biology , pi3k/akt/mtor pathway , microbiology and biotechnology , skeletal muscle , protein kinase b , signal transduction , chemistry , endocrinology , receptor , postsynaptic potential , biochemistry
The trophic mechanisms by which motor nerves impart growth of skeletal muscle targets are rudimentary. We have shown that muscles exposed to increased neural activation and contractile loading fail to hypertrophy if not provided with suitable trophic chemical support from their motor nerves. When trophically‐challenged and overloaded muscles are treated with recombinant neural agrin, hypertrophic growth is rescued via p70 S6K signaling. Agrin therapy induced extensive phosphorylation of p70 S6K, but not via Akt or PDK‐1 as upstream modulators, suggesting neural agrin binding to its receptor activates p70 S6K, either directly, or indirectly via other yet to be identified signaling elements. We also assessed the contribution of neural activity and nerve trophic factors on p70 S6K phosphorylation in muscles either denervated or paralyzed by TTX‐inactivation of the sciatic nerve. We found p70 S6K to be fully dephosphorylated after denervation but not after TTX, suggesting nerve trophic factors to be major modulators of this signaling pathway. Considering muscle growth is regulated in part by translational mechanisms downstream of Akt/mTOR and by transcriptional mechanisms associated with muscle activation, our data suggest agrin may cooperate with these signaling pathways to converge upon p70 S6K to potentiate translational control of muscle growth. Supported by NSERC and the CRC to RNM.