title: Exercise and diabetes have opposite effects on the assembly and O-GlcNAc modification of the mSin3A/HDAC1/2 complex in the heart.
abstract: BACKGROUND
  Exercise causes physiological cardiac hypertrophy and benefits the diabetic heart. Mammalian switch-independent 3A (mSin3A) and histone deacetylases (HDACs) 1 and 2 regulate hypertrophic genes through associations with the DNA binding proteins repressor element-1 silencing transcription factor (REST) and O-linked β-N-acetylglucosamine transferase (OGT). O-linked β-N-acetylglucosamine (O-GlcNAc) is a glucose derivative that is chronically elevated in diabetic hearts, and a previous study showed that exercise reduces cardiac O-GlcNAc. We hypothesized that O-GlcNAc and OGT would physically associate with mSin3A/HDAC1/2 in the heart, and that this interaction would be altered by diabetes and exercise.
  
  
  METHODS
  8-week-old type 2 diabetic db/db (db) and non-diabetic C57 mice were randomized to treadmill exercise or sedentary groups for 1 or 4 weeks.
  
  
  RESULTS
  O-GlcNAc was significantly higher in db hearts and increased with exercise. Db hearts showed lower levels of mSin3A, HDAC1, and HDAC2 protein, but higher levels of HDAC2 mRNA and HDAC1/2 deacetylase activity. Elevated HDAC activity was associated with significantly blunted expression of α-actin and brain natriuretic peptide in db hearts. In sedentary db hearts, co-immunoprecipitation assays showed that mSin3A and OGT were less associated with HDAC1 and HDAC2, respectively, compared to sedentary C57 controls; however, exercise removed these differences.
  
  
  CONCLUSIONS
  These data indicate that diabetes and exercise oppositely affect interactions between pro-hypertrophic transcription factors, and suggest that an increase in total cardiac O-GlcNAc is a mechanism by which exercise benefits type 2 diabetic hearts.
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Cox
authors.forename: Susan A
authors.initials: SA
authors.lastname: Marsh
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D006332:Cardiomegaly / Q000378:metabolism / Q000628:therapy; D003924:Diabetes Mellitus, Type 2 / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D058065:Diabetic Cardiomyopathies / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D004195:Disease Models, Animal; D005081:Exercise Therapy; D005786:Gene Expression Regulation; D006031:Glycosylation; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism*; D056464:Histone Deacetylase 2 / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism*; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism; D009765:Obesity / Q000378:metabolism / Q000628:therapy; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D012420:Running; D057185:Sedentary Behavior; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D013997:Time Factors
chemical_list: D001786:Blood Glucose; D012333:RNA, Messenger; D012097:Repressor Proteins; C099683:SIN3A transcription factor; D017351:N-Acetylglucosaminyltransferases; C063057:UDP-N-acetylglucosamine-peptide beta-N-acetylglucosaminyltransferase; C484389:Hdac1 protein, mouse; C533424:Hdac2 protein, mouse; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D000117:Acetylglucosamine