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.
Berdeaux
Rebecca
R
Peptide Biology Laboratories, Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Goebel
Naomi
N
Banaszynski
Laura
L
Takemori
Hiroshi
H
Wandless
Thomas
T
Shelton
G Diane
GD
Montminy
Marc
M
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics; D015444:Exercise / Q000502:physiology; D005786:Gene Expression Regulation; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D064326:MEF2 Transcription Factors; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000502:physiology; D032342:Muscle Cells / Q000166:cytology*; D018482:Muscle, Skeletal / Q000166:cytology* / Q000502:physiology*; D009137:Muscular Dystrophy, Animal / Q000235:genetics; D018006:Myogenic Regulatory Factors / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*
C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D012097:Repressor Proteins; D017346:Protein Serine-Threonine Kinases; C495376:Sik1 protein, mouse; C120299:Sik1 protein, rat; C533424:Hdac2 protein, mouse; C533426:Hdac2 protein, rat; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases; D002118:Calcium