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SIK1 is a class II HDAC kinase that promotes survival of skeletal myocytes


During physical exercise, increases in motor neuron activity stimulate the expression of muscle-specific genes through the myocyte enhancer factor 2 (MEF2) family of transcription factors. Elevations in intracellular calcium increase MEF2 activity via the phosphorylation-dependent inactivation of class II histone deacetylases (HDACs). In studies to determine the role of the cAMP responsive element binding protein (CREB) in skeletal muscle, we found that mice expressing a dominant-negative CREB transgene (M-ACREB mice) exhibited a dystrophic phenotype along with reduced MEF2 activity. Class II HDAC phosphorylation was decreased in M-ACREB myofibers due to a reduction in amounts of Snf1lk (encoding salt inducible kinase, SIK1), a CREB target gene that functions as a class II HDAC kinase. Inhibiting class II HDAC activity either by viral expression of Snf1lk or by the administration of a small molecule antagonist improved the dystrophic phenotype in M-ACREB mice, pointing to an important role for the SIK1-HDAC pathway in regulating muscle function.

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Figure 1: Muscle A-CREB (M-ACREB) mice exhibit a dystrophic phenotype.
Figure 2: Reduced phosphorylation of class II HDACs in M-ACREB mice.
Figure 3: CREB stimulates expression of the Ser/Thr kinase SIK1 in skeletal myocytes.
Figure 4: SIK1 regulates MEF2 activity by phosphorylating class II HDACs.
Figure 5: Disruption of class II HDAC activity rescues the dystrophic phenotype in M-ACREB mice.
Figure 6: Model showing the proposed role of CREB in skeletal muscle.


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We thank the members of the Montminy lab for helpful discussions, N. Huff for technical assistance with the histology, M. Scadeng for X-ray analysis, and X. Zhang and L. Ouyang for help with microarray experiments. We thank E. Olson (University of Texas Southwestern Medical Center) for Mef2-luciferase and Mef2c expression constructs, T. McKinsey (Myogen, Inc.) for antibodies to pHDAC, M. Okamoto (Osaka Medical School, Japan) for antibodies to SIK1, and T.P. Yao (Duke University) for recombinant HDAC4. We also thank M. Weitzman (the Salk Institute) for AAV reagents. This work was supported by grants from the National Institutes of Health (National Institute of General Medical Sciences and National Institute of Diabetes and Digestive and Kidney Diseases) and the Kieckhefer Foundation.

Author information

Authors and Affiliations



R.B. performed animal and cell culture experiments. N.G. performed histological analyses and aided in biochemical studies. L.B. and T.W. provided expertise on the Shld-1 expression system. H.T. provided expertise and reagents for SIK1 analysis. G.D.S. performed histochemical analyses and provided expertise on muscle pathology. Experimental design, data analysis and manuscript preparation were carried out by R.B. and M.M.

Corresponding author

Correspondence to Marc Montminy.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

M-ACREB transgenic animals develop progressive muscular dystrophy. (PDF 155 kb)

Supplementary Fig. 2

Absence of fibrosis, changes in fiber-type distribution and metabolic storage products in M-ACREB transgenic mice. (PDF 289 kb)

Supplementary Fig. 3

MEF2 target gene expression is reduced in skeletal muscles of M-ACREB mice. (PDF 61 kb)

Supplementary Fig. 4

SIK1 protein is induced by cAMP and reduced in M-ACREB tissue. (PDF 133 kb)

Supplementary Fig. 5

SIK1 phosphorylates class II HDACs. (PDF 137 kb)

Supplementary Fig. 6

RNAi mediated knockdown of SIK1 induces necrosis of C2C12 cells. (PDF 153 kb)

Supplementary Fig. 7

AAV-mediated delivery of SIK1 rescues the dystrophic phenotype in MACREB transgenic muscle. (PDF 174 kb)

Supplementary Methods (PDF 82 kb)

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Berdeaux, R., Goebel, N., Banaszynski, L. et al. SIK1 is a class II HDAC kinase that promotes survival of skeletal myocytes. Nat Med 13, 597–603 (2007).

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