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Histone deacetylase 5 regulates Interleukin 6 secretion and insulin action in skeletal muscle

ABSTRACT: Physical exercise training is associated with increased glucose uptake in skeletal muscle and improved glycemic control. Histone Deacetylases (HDACs) are divided into three structurally defined subclasses and are critical for transcriptional regulation, cell cycle progression, and developmental events. HDAC5, a class IIa histone deacetylase regulates transcription of the insulin-responsive glucose transporter GLUT4 in cultured muscle cells. Interleukin-6 (IL-6) is a prototypical cytokine featuring functional redundancy and pleiotropy. Under healthy conditions the serum level of IL-6 is less than 4 pg/ml. The cytokine IL-6 was the first myokine found to be secreted into bloodstream in response to muscle contractions. Exercise intervention induce secretion of muscle-derived IL-6, leading to an acute and rebuses increase of systemic IL-6 up to 100-fold higher than basal levels a far greater increase than that of any other cytokine that has been measured. HDAC5 depletion in skeletal muscle lead to increased glucose uptake that was driven by IL-6 and p-AKT signaling. We specifically revealed that HDAC5 binds to the IL-6 promoter to regulate its transcription. These effects were facilitated by exercise and muscle contractions. In summary, we identified HDAC5 as a negative regulator of IL-6 synthesis and release in skeletal muscle. HDAC5 may exert beneficial effects through two different mechanisms, transcriptional control of genes required for glucose disposal and utilization, and HDAC5-dependent IL-6 signaling in order to improve glucose uptake in muscle in response to exercise.

ORGANISM(S): Mus musculus

PROVIDER: GSE150485 | GEO | 2020/10/02

REPOSITORIES: GEO

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