A calcineurin-dependent transcriptional pathway controls skeletal muscle fiber type
- PMID: 9716403
- PMCID: PMC317085
- DOI: 10.1101/gad.12.16.2499
A calcineurin-dependent transcriptional pathway controls skeletal muscle fiber type
Abstract
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.
Figures
![Figure 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/317085/bin/gad.17f1.gif)
![Figure 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/317085/bin/gad.17f2a.gif)
![Figure 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/317085/bin/gad.17f2a.gif)
![Figure 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/317085/bin/gad.17f2a.gif)
![Figure 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/317085/bin/gad.17f3a.gif)
![Figure 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/317085/bin/gad.17f3a.gif)
![Figure 4](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/317085/bin/gad.17f4a.gif)
![Figure 4](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/317085/bin/gad.17f4a.gif)
![Figure 5](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/317085/bin/gad.17f5.gif)
![Figure 6](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/317085/bin/gad.17f6a.gif)
![Figure 6](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/317085/bin/gad.17f6a.gif)
Similar articles
-
Signaling pathways in activity-dependent fiber type plasticity in adult skeletal muscle.J Muscle Res Cell Motil. 2005;26(1):13-21. doi: 10.1007/s10974-005-9002-0. Epub 2005 Oct 14. J Muscle Res Cell Motil. 2005. PMID: 16096682 Review.
-
NFAT is a nerve activity sensor in skeletal muscle and controls activity-dependent myosin switching.Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10590-5. doi: 10.1073/pnas.0308035101. Epub 2004 Jul 9. Proc Natl Acad Sci U S A. 2004. PMID: 15247427 Free PMC article.
-
Matching of calcineurin activity to upstream effectors is critical for skeletal muscle fiber growth.J Cell Biol. 2000 Oct 30;151(3):663-72. doi: 10.1083/jcb.151.3.663. J Cell Biol. 2000. PMID: 11062266 Free PMC article.
-
MEF2 responds to multiple calcium-regulated signals in the control of skeletal muscle fiber type.EMBO J. 2000 May 2;19(9):1963-73. doi: 10.1093/emboj/19.9.1963. EMBO J. 2000. PMID: 10790363 Free PMC article.
-
Muscle development: electrical control of gene expression.Curr Biol. 1998 Dec 3;8(24):R892-4. doi: 10.1016/s0960-9822(07)00554-4. Curr Biol. 1998. PMID: 9843678 Review.
Cited by
-
Developmental, Physiological and Phylogenetic Perspectives on the Expression and Regulation of Myosin Heavy Chains in Craniofacial Muscles.Int J Mol Sci. 2024 Apr 21;25(8):4546. doi: 10.3390/ijms25084546. Int J Mol Sci. 2024. PMID: 38674131 Free PMC article. Review.
-
Dietary Chitosan Oligosaccharide Supplementation Improves Meat Quality by Improving Antioxidant Capacity and Fiber Characteristics in the Thigh Muscle of Broilers.Antioxidants (Basel). 2024 Mar 18;13(3):366. doi: 10.3390/antiox13030366. Antioxidants (Basel). 2024. PMID: 38539899 Free PMC article.
-
Mechanism of post-tetanic depression of slow muscle fibres.J Comp Physiol B. 2024 Feb;194(1):41-45. doi: 10.1007/s00360-024-01536-6. Epub 2024 Feb 12. J Comp Physiol B. 2024. PMID: 38347296
-
Cognitive Dysfunction and Exercise: From Epigenetic to Genetic Molecular Mechanisms.Mol Neurobiol. 2024 Jan 30. doi: 10.1007/s12035-024-03970-7. Online ahead of print. Mol Neurobiol. 2024. PMID: 38286967 Review.
-
CHCHD4-TRIAP1 regulation of innate immune signaling mediates skeletal muscle adaptation to exercise.Cell Rep. 2024 Jan 23;43(1):113626. doi: 10.1016/j.celrep.2023.113626. Epub 2023 Dec 28. Cell Rep. 2024. PMID: 38157298 Free PMC article.
References
-
- Aramburu J, Garcia-Cozar F, Raghavan A, Okamura H, Rao A, Hogan GG. Selective inhibition of NFAT activation by a peptide spanning the calcineurin targeting site of NFAT. Mol Cell. 1998;1:627–637. - PubMed
-
- Bassel-Duby R, Grohe CM, Jessen ME, Parsons WJ, Richardson JA, Chao R, Grayson J, Ring WS, Williams RS. Sequence elements required for transcriptional activity of the human myoglobin promoter in intact myocardium. Circ Res. 1993;73:360–366. - PubMed
-
- Black BL, Olson EN. Transcriptional control of muscle development by myocyte enhancer factor-2 (MEF2) proteins. Annu Rev Cell Dev Biol. 1998;14:167–196. - PubMed
-
- Booth FW, Baldwin KM. Muscle plasticity: Energy demand and supply processes. In: Rowell LB, Shepard JT, editors. The handbook of physiology: Integration of motor, circulatory, respiratory and metabolic control during exercise. Bethesda, MD: American Physiology Society; 1996. pp. 1075–1123.
-
- Brooke MH, Kaiser KK. Muscle fiber types: How many and what kind? Arch Neurol. 1970;23:369–379. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources