Suppression of protein kinase C theta contributes to enhanced myogenesis In vitro via IRS1 and ERK1-2 phosphorylationReport as inadecuate

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BMC Cell Biology

, 14:39

Cell signaling pathways and networks


BackgroundDifferentiation and fusion of skeletal muscle myoblasts into multi-nucleated myotubes is required for neonatal development and regeneration in adult skeletal muscle. Herein, we report novel findings that protein kinase C theta PKCθ regulates myoblast differentiation via phosphorylation of insulin receptor substrate-1 and ERK1-2.

ResultsIn this study, PKCθ knockdown PKCθ myotubes had reduced inhibitory insulin receptor substrate-1 ser1095 phosphorylation, enhanced myoblast differentiation and cell fusion, and increased rates of protein synthesis as determined by H phenylalanine incorporation. Phosphorylation of insulin receptor substrate-1 ser632-635 and extracellular signal-regulated kinase1-2 ERK1-2 was increased in PKCθ cells, with no change in ERK5 phosphorylation, highlighting a PKCθ-regulated myogenic pathway. Inhibition of PI3-kinase prevented cell differentiation and fusion in control cells, which was attenuated in PKCθ cells. Thus, with reduced PKCθ, differentiation and fusion occur in the absence of PI3-kinase activity. Inhibition of the ERK kinase, MEK1-2, impaired differentiation and cell fusion in control cells. Differentiation was preserved in PKCθ cells treated with a MEK1-2 inhibitor, although cell fusion was blunted, indicating PKCθ regulates differentiation via IRS1 and ERK1-2, and this occurs independently of MEK1-2 activation.

ConclusionCellular signaling regulating the myogenic program and protein synthesis are complex and intertwined. These studies suggest that PKCθ regulates myogenic and protein synthetic signaling via the modulation of IRS1and ERK1-2 phosphorylation. Myotubes lacking PKCθ had increased rates of protein synthesis and enhanced myotube development despite reduced activation of the canonical anabolic-signaling pathway. Further investigation of PKCθ regulated signaling may reveal important interactions regulating skeletal muscle health in an insulin resistant state.

KeywordsProtein kinase C Myoblast differentiation Myoblast fusion Insulin receptor substrate AbbreviationsPKCθProtein kinase C theta

PKCΔProtein kinase C delta

IRInsulin receptor

IRS1Insulin receptor substrate-1

AKTAlso known as protein kinase B PKB

ERKExtracellular signal-related kinase

MEK1-2Mitogen activated ERK kinase

PI3-kinasePhosphoinositide 3-kinase

mTORMammalian target of rapamycin

shRNAShort hairpin RNA.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2121-14-39 contains supplementary material, which is available to authorized users.

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Author: Joseph S Marino - Terry D HindsJr. - Rachael A Potter - Eric Ondrus - Jeremy L Onion - Abigail Dowling - Thomas J McLo


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