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CLOCK and BMAL1 regulate MyoD and are necessary for maintenance of skeletal muscle phenotype and function.
Proc Natl Acad Sci U S A. 2010 Nov 02; 107(44):19090-5.PN

Abstract

MyoD, a master regulator of myogenesis, exhibits a circadian rhythm in its mRNA and protein levels, suggesting a possible role in the daily maintenance of muscle phenotype and function. We report that MyoD is a direct target of the circadian transcriptional activators CLOCK and BMAL1, which bind in a rhythmic manner to the core enhancer of the MyoD promoter. Skeletal muscle of Clock(Δ19) and Bmal1(-/-) mutant mice exhibited ∼30% reductions in normalized maximal force. A similar reduction in force was observed at the single-fiber level. Electron microscopy (EM) showed that the myofilament architecture was disrupted in skeletal muscle of Clock(Δ19), Bmal1(-/-), and MyoD(-/-) mice. The alteration in myofilament organization was associated with decreased expression of actin, myosins, titin, and several MyoD target genes. EM analysis also demonstrated that muscle from both Clock(Δ19) and Bmal1(-/-) mice had a 40% reduction in mitochondrial volume. The remaining mitochondria in these mutant mice displayed aberrant morphology and increased uncoupling of respiration. This mitochondrial pathology was not seen in muscle of MyoD(-/-) mice. We suggest that altered expression of both Pgc-1α and Pgc-1β in Clock(Δ19) and Bmal1(-/-) mice may underlie this pathology. Taken together, our results demonstrate that disruption of CLOCK or BMAL1 leads to structural and functional alterations at the cellular level in skeletal muscle. The identification of MyoD as a clock-controlled gene provides a mechanism by which the circadian clock may generate a muscle-specific circadian transcriptome in an adaptive role for the daily maintenance of adult skeletal muscle.

Authors+Show Affiliations

School of Kinesiology, University of Illinois, Chicago, IL 60609, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20956306

Citation

Andrews, Jessica L., et al. "CLOCK and BMAL1 Regulate MyoD and Are Necessary for Maintenance of Skeletal Muscle Phenotype and Function." Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 44, 2010, pp. 19090-5.
Andrews JL, Zhang X, McCarthy JJ, et al. CLOCK and BMAL1 regulate MyoD and are necessary for maintenance of skeletal muscle phenotype and function. Proc Natl Acad Sci USA. 2010;107(44):19090-5.
Andrews, J. L., Zhang, X., McCarthy, J. J., McDearmon, E. L., Hornberger, T. A., Russell, B., Campbell, K. S., Arbogast, S., Reid, M. B., Walker, J. R., Hogenesch, J. B., Takahashi, J. S., & Esser, K. A. (2010). CLOCK and BMAL1 regulate MyoD and are necessary for maintenance of skeletal muscle phenotype and function. Proceedings of the National Academy of Sciences of the United States of America, 107(44), 19090-5. https://doi.org/10.1073/pnas.1014523107
Andrews JL, et al. CLOCK and BMAL1 Regulate MyoD and Are Necessary for Maintenance of Skeletal Muscle Phenotype and Function. Proc Natl Acad Sci USA. 2010 Nov 2;107(44):19090-5. PubMed PMID: 20956306.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - CLOCK and BMAL1 regulate MyoD and are necessary for maintenance of skeletal muscle phenotype and function. AU - Andrews,Jessica L, AU - Zhang,Xiping, AU - McCarthy,John J, AU - McDearmon,Erin L, AU - Hornberger,Troy A, AU - Russell,Brenda, AU - Campbell,Kenneth S, AU - Arbogast,Sandrine, AU - Reid,Michael B, AU - Walker,John R, AU - Hogenesch,John B, AU - Takahashi,Joseph S, AU - Esser,Karyn A, Y1 - 2010/10/18/ PY - 2010/10/20/entrez PY - 2010/10/20/pubmed PY - 2010/12/14/medline SP - 19090 EP - 5 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc. Natl. Acad. Sci. U.S.A. VL - 107 IS - 44 N2 - MyoD, a master regulator of myogenesis, exhibits a circadian rhythm in its mRNA and protein levels, suggesting a possible role in the daily maintenance of muscle phenotype and function. We report that MyoD is a direct target of the circadian transcriptional activators CLOCK and BMAL1, which bind in a rhythmic manner to the core enhancer of the MyoD promoter. Skeletal muscle of Clock(Δ19) and Bmal1(-/-) mutant mice exhibited ∼30% reductions in normalized maximal force. A similar reduction in force was observed at the single-fiber level. Electron microscopy (EM) showed that the myofilament architecture was disrupted in skeletal muscle of Clock(Δ19), Bmal1(-/-), and MyoD(-/-) mice. The alteration in myofilament organization was associated with decreased expression of actin, myosins, titin, and several MyoD target genes. EM analysis also demonstrated that muscle from both Clock(Δ19) and Bmal1(-/-) mice had a 40% reduction in mitochondrial volume. The remaining mitochondria in these mutant mice displayed aberrant morphology and increased uncoupling of respiration. This mitochondrial pathology was not seen in muscle of MyoD(-/-) mice. We suggest that altered expression of both Pgc-1α and Pgc-1β in Clock(Δ19) and Bmal1(-/-) mice may underlie this pathology. Taken together, our results demonstrate that disruption of CLOCK or BMAL1 leads to structural and functional alterations at the cellular level in skeletal muscle. The identification of MyoD as a clock-controlled gene provides a mechanism by which the circadian clock may generate a muscle-specific circadian transcriptome in an adaptive role for the daily maintenance of adult skeletal muscle. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/20956306/CLOCK_and_BMAL1_regulate_MyoD_and_are_necessary_for_maintenance_of_skeletal_muscle_phenotype_and_function_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=20956306 DB - PRIME DP - Unbound Medicine ER -