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.
Chin
E R
ER
Departments of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75235, USA.
Olson
E N
EN
Richardson
J A
JA
Yang
Q
Q
Humphries
C
C
Shelton
J M
JM
Wu
H
H
Zhu
W
W
Bassel-Duby
R
R
Williams
R S
RS
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