Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text Full Text (PDF, 462K) PPT slides of all figures Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Dunn, S. E. Articles by Michel, R. N. Search for Related Content PubMed PubMed Citation Articles by Dunn, S. E. Articles by Michel, R. N. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Hazardous Substances DB CYCLOSPORIN A Social Bookmarking                            What's this?

© The Rockefeller University Press, 0021-9525/2000//663 $5.00
The Journal of Cell Biology, Volume 151, Number 3, , 2000 663-672

Matching of Calcineurin Activity to Upstream Effectors Is Critical for Skeletal Muscle Fiber Growth

^a Neuromuscular Research Laboratory, Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Ontario P3E 2C6, Canada
^b Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75235-8573
Department of Chemistry and Biochemistry, Laurentian University, Ramsey Lk. Road, Sudbury, Ontario, Canada, P3E 2C6.(705) 675-1151 (ext

Calcineurin-dependent pathways have been implicated in the hypertrophic response of skeletal muscle to functional overload (OV) (Dunn, S.E., J.L. Burns, and R.N. Michel. 1999. J. Biol. Chem. 274:21908–21912). Here we show that skeletal muscles overexpressing an activated form of calcineurin (CnA*) exhibit a phenotype indistinguishable from wild-type counterparts under normal weightbearing conditions and respond to OV with a similar doubling in cell size and slow fiber number. These adaptations occurred despite the fact that CnA* muscles displayed threefold higher calcineurin activity and enhanced dephosphorylation of the calcineurin targets NFATc1, MEF2A, and MEF2D. Moreover, when calcineurin signaling is compromised with cyclosporin A, muscles from OV wild-type mice display a lower molecular weight form of CnA, originally detected in failing hearts, whereas CnA* muscles are spared this manifestation. We also show that OV-induced growth and type transformations are prevented in muscle fibers of transgenic mice overexpressing a peptide that inhibits calmodulin from signaling to target enzymes. Taken together, these findings provide evidence that both calcineurin and its activity-linked upstream signaling elements are crucial for muscle adaptations to OV and that, unless significantly compromised, endogenous levels of this enzyme can accommodate large fluctuations in upstream calcium-dependent signaling events.

Key Words: calmodulin • MEF2 • NFAT • hypertrophy • calcium signaling

© 2000 The Rockefeller University Press

Abbreviations used in this paper: CaM, calmodulin; CnA, catalytic subunit of calcineurin; CnA*, activated form of the catalytic subunit of calcineurin; CsA, cyclosporin A; MCK, muscle creatine kinase; MEF2, myocyte enhancer factor 2; MHC, myosin heavy chain; MLC, myosin light chain; NFAT, nuclear factor of activated T cells; OV, overload; Tg, transgenic; TnIf, troponin I fast; TnIs, troponin I slow.

CiteULike

Complore

Connotea

Del.icio.us

Digg

Facebook

Reddit

Technorati

Twitter

Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents