A calcineurin-dependent transcriptional pathway controls skeletal muscle fiber type.
Slow- and fast-twitch myofibers of adult skeletal muscles express unique sets of muscle-specific genes, and these distinctive programs of gene expression are controlled by variations in motor neuron activity. It is well established that, as a consequence of more frequent neural stimulation, slow fibers maintain higher levels of intracellular free calcium than fast fibers, but the mechanisms by which calcium may function as a messenger linking nerve activity to changes in gene expression in skeletal muscle have been unknown. Here, fiber-type-specific gene expression in skeletal muscles is shown to be controlled by a signaling pathway that involves calcineurin, a cyclosporin-sensitive, calcium-regulated serine/threonine phosphatase. Activation of calcineurin in skeletal myocytes selectively up-regulates slow-fiber-specific gene promoters. Conversely, inhibition of calcineurin activity by administration of cyclosporin A to intact animals promotes slow-to-fast fiber transformation. Transcriptional activation of slow-fiber-specific transcription appears to be mediated by a combinatorial mechanism involving proteins of the NFAT and MEF2 families. These results identify a molecular mechanism by which different patterns of motor nerve activity promote selective changes in gene expression to establish the specialized characteristics of slow and fast myofibers.
Departments of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75235, USA.
E R
ER
Chin
E N
EN
Olson
J A
JA
Richardson
Q
Q
Yang
C
C
Humphries
J M
JM
Shelton
H
H
Wu
W
W
Zhu
R
R
Bassel-Duby
R S
RS
Williams
D016475:3T3 Cells; D000818:Animals; D001665:Binding Sites; D019703:Calcineurin / Q000502:physiology*; D065095:Calcineurin Inhibitors; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D051379:Mice; D009046:Motor Neurons / Q000502:physiology; D018656:Muscle Fibers, Fast-Twitch / Q000502:physiology; D018485:Muscle Fibers, Skeletal / Q000502:physiology*; D018657:Muscle Fibers, Slow-Twitch / Q000502:physiology; D018482:Muscle, Skeletal / Q000502:physiology*; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic; D051381:Rats; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D065095:Calcineurin Inhibitors; D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors; D016572:Cyclosporine; D019703:Calcineurin; D002118:Calcium