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

Abstract

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 this 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 wild-type (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 conducted to analyze Il6 promoter activity using H3K9ac and HDAC5 antibodies. Results Global transcriptome analysis of Hdac5 KO gastrocnemius muscle demonstrated 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 that 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 demonstrated increased activation-associated histone marker AcH3K9 in Hdac5 -deficient muscle cells. Exercise intervention of HDAC5 KO mice resulted in improved systemic glucose tolerance as compared to WT controls. Conclusions 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 to improve glucose uptake in muscle in response to exercise.

Independent association of general and central adiposity with risk of gallstone disease: observational and genetic analyses

“…Lenoir et al found an increase in insulin-producing b-cell mass in the pancreas of HDAC5-knockout mice while a decrease in HDAC5-overexpressed mice, demonstrating a suppressing role of HDAC5 in insulin production (35). Such an effect on insulin action was also observed in muscle cells (36,37). Studies have shown that insulin resistance is associated with both GSD and central obesity.…”

Electrical Stimulation Increases the Secretion of Cardioprotective Extracellular Vesicles from Cardiac Mesenchymal Stem Cells

“…Epigenetic regulation might also be involved in ELSM-induced gene regulation. Klymenk O. et al [ 64 ] reported that ELSM-induced interleukin 6 (IL6) transcription was enhanced in histone deacetylase 5(HDAC5)-deficient C2C12 myotubes. Recent studies have shown that EV-derived microRNAs contribute to cardioprotection by acting as anti-apoptotic mediators [ 65 , 66 ].…”

The role of exercise-induced myokines in promoting angiogenesis

“…In PRMT1-deficent mice, IL-6 expression in the liver was decreased, suggesting that PRMT1 is involved in the regulation of IL-6 expression (Zhao et al, 2019). Klymenko et al (Klymenko et al, 2020) found that HDAC5 can negatively regulate IL-6 gene expression and then affect glucose uptake in skeletal muscle cells. By electrically stimulating C2C12 cells to generate a muscle contraction model, it was found that IL-6 expression in HDAC5-deficient myocytes was higher than that in wildtype cells, suggesting that HDAC5 was also involved in the regulation of exercise-induced IL-6 expression.…”