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© 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.

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