Matching of calcineurin activity to upstream effectors is critical for skeletal muscle fiber growth.
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.
Dunn
S E
SE
Neuromuscular Research Laboratory, Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Ontario P3E 2C6, Canada.
Chin
E R
ER
Michel
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RN
D000222:Adaptation, Physiological; D000818:Animals; D015153:Blotting, Western; D001835:Body Weight; D019703:Calcineurin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D002148:Calmodulin-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002452:Cell Count; D048429:Cell Size; D016572:Cyclosporine / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D015870:Gene Expression; D014644:Genetic Variation / Q000235:genetics; D006984:Hypertrophy; D064326:MEF2 Transcription Factors; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008970:Molecular Weight; D024510:Muscle Development; D018656:Muscle Fibers, Fast-Twitch / Q000166:cytology / Q000502:physiology; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000201:enzymology* / Q000502:physiology*; D018657:Muscle Fibers, Slow-Twitch / Q000166:cytology / Q000502:physiology; D018482:Muscle, Skeletal / Q000166:cytology / Q000201:enzymology* / Q000254:growth & development*; D018006:Myogenic Regulatory Factors; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D009929:Organ Size; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism; D016474:Weight-Bearing / Q000502:physiology
D002148:Calmodulin-Binding Proteins; D004268:DNA-Binding Proteins; D064326:MEF2 Transcription Factors; C578036:Mef2a protein, mouse; C578044:Mef2d protein, mouse; D018006:Myogenic Regulatory Factors; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D016572:Cyclosporine; D019703:Calcineurin