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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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Secreted Protein Acidic and Rich in Cysteine Improves Glucose Tolerance via AMP-activated Protein Kinase Activation

Project description:Metabolic dysfunction of skeletal muscle is often prevalent at an early stage in the development of several non-communicable diseases. Here, we investigated the effect of a myokine, secreted protein acidic and rich in cysteine (SPARC), on glucose tolerance in human and mouse skeletal muscles. SPARC knockout mice showed marked decreases in parameters for whole-body glucose metabolism, along with reduced phosphorylation of AMPK and Akt in skeletal muscle tissues compared with wild-type mice. Furthermore, mice injected with SPARC showed improved glucose tolerance concomitant with AMPK activation. Exogenous SPARC treatment accelerated glucose uptake in muscle tissues isolated from wild-type mice but not from AMPKγ3 knockout mice. In muscle cells, SPARC increased glucose uptake concomitant with AMPK activation, mediated by a calcium-dependent signal. Chronic treatment of SPARC restored metabolic functions in diet-induced obese mice. These findings suggest that SPARC improves glucose metabolism via AMPK activation in skeletal muscle, providing mechanistic insights on exercise-induced metabolic benefits and physical inactivity-induced glucose intolerance.

2019-06-03 | GSE93546 | GEO

Human skeletal muscle biopsies from a 3h IL-6 infusion

2008-05-28 | GSE10685 | GEO

NURR1 activation in skeletal muscle controls systemic energy homeostasis (RNA-seq)

Project description:Skeletal muscle plays a central role in the control of metabolism and exercise tolerance. Analysis of muscle enhancers activated after exercise in mice revealed the orphan nuclear receptor NURR1/NR4A2 as a prominent component of exercise-responsive enhancers. We show that exercise enhances the expression of NURR1 and transgenic overexpression of NURR1 in skeletal muscle confers an endurance phenotype in mice. NURR1 expression in skeletal muscle is also sufficient to prevent hyperglycemia and hepatic steatosis by enhancing muscle glucose uptake and storage as glycogen. Furthermore, treatment of obese mice with putative NURR1 agonists increases energy expenditure, improves glucose tolerance, and confers a lean phenotype, mimicking the effects of exercise. These findings identify a key role for NURR1 in governance of skeletal muscle glucose metabolism and reveal a transcriptional link between exercise and metabolism. Our findings also identify NURR1 agonists as possible exercise mimetics with the potential to ameliorate obesity and other metabolic abnormalities.

2019-08-01 | GSE130838 | GEO

NURR1 activation in skeletal muscle controls systemic energy homeostasis (ChIP-seq)

2019-08-01 | GSE130839 | GEO

Human skeletal muscle biopsies from a 3h IL-6 infusion

Project description:Skeletal muscle has been identified as a secretory organ. We hypothesized that IL-6, a cytokine secreted from skeletal muscle during exercise, could induce production of other secreted factors in skeletal muscle. Keywords: Human skeletal muscle time course response to IL-6 infusion IL-6 was infused for 3 h into healthy young males (n=7) and muscle biopsies obtained at time points 0, 3 and 6 h in these individuals. Affymetrix microarray analysis of gene expression profiling in muscle were carried out on 3 randomly chosen subjects.

2008-05-27 | E-GEOD-10685 | biostudies-arrayexpress

Effect of Disease and Exercise in Skeletal Muscle of Patients with Peripheral Artery Disease

Project description:PAD is associated with reduced uptake of glucose and insulin resistance in skeletal muscle. In this study, we look at the effect of exercise on gene expression in patients with PAD.

2021-04-30 | GSE113873 | GEO

RNA-Seq of Myf6-knockout versus Wild-type satellite cells

Project description:In metazoans, skeletal muscle evolved to contract and produce force. Recent experimental evidence, however, suggests that skeletal muscle has also acquired endocrine functions and produces a vast array of muscle-derived cytokines and growth factors, collectively called myokines. The mechanisms that regulate myokine production and their effect on the resident stem cell population inskeletal muscle remain unknown. Here, we report that in adult skeletal muscle, Myf6/MRF4 is a major regulator of myokine expression. Genetic deletion of Myf6 in skeletal muscle leads to reduction of the muscle stem cell (MuSCs) pool in adult mice in a myokine-dependent manner but, surprisingly, does not disrupt muscle differentiation. Using ChIP-Seq and gene expression analyses of myogenic factors, we show that Myf6/MRF4 is a direct regulator of many myokines and muscle-secreted proteins, including ligands for canonical signaling pathways such as EGFR and VEGFR. Consequently, in Myf6-deficient animals,MuSCs increasingly break quiescence, but can nevertheless undergo differentiation. Lastly, we show that Myf6 and its gene network rapidly respondto aerobic and anaerobic exercise. Together, these findings indicate that control of myokine signaling by Myf6 is critical to maintain muscle stem cell pool and skeletal muscle function via myokine signaling.

2020-10-02 | GSE133505 | GEO

Myf6/MRF4 Mediated Myokine Signaling is Required for the Maintenance of the Adult Skeletal Muscle Stem Cell Pool

Project description:In metazoans, skeletal muscle evolved to contract and to produce force. Recent experimental evidence suggests, however, that skeletal muscle has also acquired endocrine functions and produces a vast array of myokines, but how myokine production is regulated and how they affect the resident stem cell population of the skeletal muscle is unknown. Here, we show that in adult skeletal muscle, Myf6/MRF4 is a major regulator of myokine expression. Genetic deletion of Myf6 in skeletal muscles leads to exhaustion of the muscle stem cell (MuSCs) pool in adult mice in a myokine-dependent manner but, surprisingly, does not disrupt muscle differentiation. Using ChIP-Seq and gene expression analyses of myogenic factors, we show that Myf6/MRF4 is essential for the transcriptional activation of many myokines and muscle-secreted proteins, including ligands for canonical signaling pathways such as EGFR, VEGFR and STAT3. Consequently, MuSCs from Myf6 knockout animals show impaired activation of those signaling pathways and exhibit impaired quiescence, defective self-renewal, but nevertheless undergo differentiation. Lastly, we show that induction of myokine expression during aerobic and anaerobic exercise closely correlates with Myf6 expression. Together, these findings indicate that control of myokine signaling by Myf6 is critical to maintain muscle stem cell pool in adult skeletal muscle.

2020-09-18 | GSE123836 | GEO

Effects of a 8-week training on human skeletal muscle

Project description:Context: Exercise training is a plausible model for identification of molecular mechanisms that cause metabolic-related changes in human skeletal muscle. Objective: The goal was to explore the molecular basis of the adaptation of skeletal muscle to exercise training. Design and Intervention: Obese male subjects were subjected to an individualized supervised training program targeted in order to optimize lipid oxidation during 8 weeks. Main Outcome Measures: Primary outcome measures were gene expression profiling of skeletal muscle. Body composition, oral glucose tolerance test, Resting metabolic rate, respiratory quotient, maximal oxygen uptake and metabolic biochemistry were also assessed.

2012-12-10 | GSE40551 | GEO

Acute molecular responses to lengthening vs shortening muscle contractions

Project description:To help elucidate mechanistic differences between lengthening and shortening muscle contractions we compared changes in gene expression within 24 h of an acute bout of each type of contraction in the quadriceps. Three healthy young men performed shortening contractions with one leg while the contralateral leg performed lengthening contractions. Biopsies were taken from both legs before exercise, 3, 6, and 24 h afterwards. Expression profiling was performed using a custom-made Affymetrix MuscleChip containing probesets of approximately 3,300 known genes and ESTs expressed in skeletal muscle. We identified 49 genes differentially regulated between the lengthening and shortening contractions. Using unsupervised hierarchical clustering, we identified four distinct clusters, three of which corresponded to unique functional categories (protein synthesis, stress response/early growth, and sarcolemmal structure). The results suggest distinct molecular pathways as early as 3 h post exercise. The molecular differences might contribute to mechanisms underlying the physiological adaptations seen with training using the two modes of exercise. Keywords: Time Series Design The hypothesis of the current study was that genes involved in hypertrophy will be differentially regulated between the two types of contractions.

2007-03-27 | E-GEOD-7286 | biostudies-arrayexpress

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