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

Nat Med. 2007 May;13(5):597-603. doi: 10.1038/nm1573. Epub 2007 Apr 29.

Abstract

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.

Publication types

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

MeSH terms

  • Animals
  • Calcium / metabolism
  • Cell Survival / physiology*
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Exercise / physiology
  • Gene Expression Regulation
  • Histone Deacetylase 2
  • Histone Deacetylases / metabolism*
  • Humans
  • MEF2 Transcription Factors
  • Mice
  • Mice, Transgenic
  • Motor Neurons / physiology
  • Muscle Cells / cytology*
  • Muscle, Skeletal / cytology*
  • Muscle, Skeletal / physiology*
  • Muscular Dystrophy, Animal / genetics
  • Myogenic Regulatory Factors / metabolism
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / metabolism*
  • Repressor Proteins / metabolism*

Substances

  • CREB1 protein, human
  • Cyclic AMP Response Element-Binding Protein
  • MEF2 Transcription Factors
  • Myogenic Regulatory Factors
  • Repressor Proteins
  • Protein-Serine-Threonine Kinases
  • Sik1 protein, mouse
  • Sik1 protein, rat
  • Hdac2 protein, mouse
  • Hdac2 protein, rat
  • Histone Deacetylase 2
  • Histone Deacetylases
  • Calcium