Abstract
BackgroundExercise 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.Methods8-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.ResultsO-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.ConclusionsThese 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.
Highlights
Exercise causes physiological cardiac hypertrophy and benefits the diabetic heart
We show that exercise increases total protein O-GlcNAcylation in the type 2 diabetic db+/db+ mouse heart, and that exercise and diabetes have reciprocal effects on the association of HDAC1 and HDAC2 with fetal gene-regulating transcription factors
The loss of HDAC2 in the diabetic heart is associated with the progression of hypertrophy in the diabetic heart, and may be involved in hypertrophy than HDAC1. These data show that exercise increases O-GlcNAc in the type 2 diabetic db mouse heart, and that components of the Mammalian switch-independent 3A (mSin3A)/HDAC1/2 chromatin-modifying complex interact with O-GlcNAc and O-linked β-N-acetylglucosamine transferase (OGT)
Summary
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). Exercise increases adult cardiac αactin [25], but does not change fetal gene expression [26], whereas type 2 diabetes reduces circulating natriuretic peptides [27,28], and blocks the activation of fetal genes by hypertrophic stimuli in vitro [29]. This suggests that fetal gene regulation in diabetic hearts is different from that of exercised hearts and non-diabetic hearts, and may underlie the hypertrophic response to these conditions
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