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

Oleksiy Klymenko, Tim Brecklinghaus, Matthias Dille, Christian Springer, ... Dhiraj G. Kabra

Objective

Physical exercise training is associated with increased glucose uptake in skeletal muscle and improved glycemic control. HDAC5, a class IIa histone deacetylase, has been shown to regulate transcription of the insulin-responsive glucose transporter GLUT4 in cultured muscle cells. In the present study, we analyzed the contribution of HDAC5 to the transcriptional network in muscle and the beneficial effect of muscle contraction and regular exercise on glucose metabolism.

Methods

HDAC5 knockout mice (KO) and wildtype (WT) littermates were trained for 8 weeks on treadmills, metabolically phenotyped, and compared to sedentary controls. Hdac5-deficient skeletal muscle and cultured Hdac5-knockdown (KD) C2C12 myotubes were utilized for studies of gene expression and glucose metabolism. Chromatin immunoprecipitation (ChIP) studies were performed to analyze Il6promoter activity using H3K9ac and HDAC5 antibodies.

Results

Global transcriptome analysis of Hdac5 KO Gastrocnemius muscle showed activation of the IL-6 signaling pathway. Accordingly, knockdown of Hdac5 in C2C12 myotubes led to higher expression and secretion of IL-6 with enhanced insulin-stimulated activation of AKT which was reversed by Il6 knockdown. Moreover, Hdac5-deficient myotubes exhibited enhanced glucose uptake, glycogen synthesis and elevated expression levels of the glucose transporter GLUT4. Transcription of Il6 was further enhanced by electrical pulse stimulation in Hdac5-deficient C2C12 myotubes. ChIP identified a ∼1 kb fragment of the Il6 promoter that interacts with HDAC5 and showed increased activation-associated histone marks AcH3K9 in Hdac5-deficient muscle cells. Finally, exercise intervention of HDAC5 KO mice resulted in improved systemic glucose tolerance as compared to WT control.

Conclusion

We identified HDAC5 as a negative epigenetic 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 cross talk in order to improve glucose uptake in muscle in response to exercise.