CLOCK and BMAL1 regulate MyoD and are necessary for maintenance of skeletal muscle phenotype and function

Jessica L. Andrews, Xiping Zhang, John J. McCarthy, Erin L. McDearmon, Troy A. Hornberger, Brenda Russell, Kenneth S. Campbell, Sandrine Arbogast, Michael B. Reid, John R. Walker, John B. Hogenesch, Joseph S. Takahashi, Karyn A. Esser

Research output: Contribution to journalArticle

152 Citations (Scopus)

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 △19 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 △19, 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△19 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△19 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.

Original languageEnglish (US)
Pages (from-to)19090-19095
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number44
DOIs
StatePublished - Nov 2 2010

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Skeletal Muscle
Maintenance
Phenotype
Muscles
Myofibrils
Electron Microscopy
Connectin
Pathology
Mitochondrial Size
Circadian Clocks
Muscle Development
Myosins
Circadian Rhythm
Transcriptome
Genes
Actins
Mitochondria
Respiration
Messenger RNA
Proteins

Keywords

  • Circadian clock
  • Mitochondria
  • Myofilaments

ASJC Scopus subject areas

  • General

Cite this

CLOCK and BMAL1 regulate MyoD and are necessary for maintenance of skeletal muscle phenotype and function. / Andrews, Jessica L.; Zhang, Xiping; McCarthy, John J.; McDearmon, Erin L.; Hornberger, Troy A.; Russell, Brenda; Campbell, Kenneth S.; Arbogast, Sandrine; Reid, Michael B.; Walker, John R.; Hogenesch, John B.; Takahashi, Joseph S.; Esser, Karyn A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 44, 02.11.2010, p. 19090-19095.

Research output: Contribution to journalArticle

Andrews, JL, Zhang, X, McCarthy, JJ, McDearmon, EL, Hornberger, TA, Russell, B, Campbell, KS, Arbogast, S, Reid, MB, Walker, JR, Hogenesch, JB, Takahashi, JS & Esser, KA 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, vol. 107, no. 44, pp. 19090-19095. https://doi.org/10.1073/pnas.1014523107
Andrews, Jessica L. ; Zhang, Xiping ; McCarthy, John J. ; McDearmon, Erin L. ; Hornberger, Troy A. ; Russell, Brenda ; Campbell, Kenneth S. ; Arbogast, Sandrine ; Reid, Michael B. ; Walker, John R. ; Hogenesch, John B. ; Takahashi, Joseph S. ; Esser, Karyn A. / CLOCK and BMAL1 regulate MyoD and are necessary for maintenance of skeletal muscle phenotype and function. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 44. pp. 19090-19095.
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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 △19 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 △19, 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△19 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△19 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.",
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AU - Hornberger, Troy A.

AU - Russell, Brenda

AU - Campbell, Kenneth S.

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AU - Reid, Michael B.

AU - Walker, John R.

AU - Hogenesch, John B.

AU - Takahashi, Joseph S.

AU - Esser, Karyn A.

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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 △19 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 △19, 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△19 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△19 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.

AB - 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 △19 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 △19, 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△19 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△19 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.

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