scholarly journals MG53 is not a critical regulator of insulin signaling pathway in skeletal muscle

2020 ◽  
Author(s):  
Clothilde Philouze ◽  
Sophie Turban ◽  
Béatrice Cremers ◽  
Audrey Caliez ◽  
Gwladys Lamarche ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Receptor ◽  
Signaling Pathway ◽  
Insulin Signaling ◽  
Insulin Response ◽  
Muscle Cells ◽  
Insulin Signaling Pathway ◽  
Akt Phosphorylation ◽  
Impaired Insulin

AbstractIn type 2 diabetes (T2D), both muscle and liver are severely resistant to insulin action. Muscle insulin resistance accounts for more than 80% of the impairment in total body glucose disposal in T2D patients and is often characterized by an impaired insulin signaling. Mitsugumin 53 (MG53), a muscle-specific TRIM family protein initially identified as a key regulator of cell membrane repair machinery has been suggested to be a critical regulator of muscle insulin signaling pathway by acting as ubiquitin E3 ligase targeting both the insulin receptor and insulin receptor substrate 1 (IRS1). Here, we show using in vitro and in vivo approaches that MG53 is not a critical regulator of insulin signaling and glucose homeostasis. First, MG53 expression is not consistently regulated in skeletal muscle from various preclinical models of insulin resistance. Second, MG53 gene knock-down in muscle cells does not lead to impaired insulin response as measured by Akt phosphorylation on Serine 473 and glucose uptake. Third, recombinant human MG53 does not alter insulin response in both differentiated C2C12 and human skeletal muscle cells. Fourth, ectopic expression of MG53 in HEK293 cells lacking endogenous MG53 expression fails to alter insulin response as measured by Akt phosphorylation. Finally, both male and female mg53 −/− mice were not resistant to high fat induced obesity and glucose intolerance compared to wild-type mice. Taken together, these results strongly suggest that MG53 is not a critical regulator of insulin signaling pathway in skeletal muscle.

scholarly journals MG53 is not a critical regulator of insulin signaling pathway in skeletal muscle

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0245179
Author(s):  
Clothilde Philouze ◽  
Sophie Turban ◽  
Beatrice Cremers ◽  
Audrey Caliez ◽  
Gwladys Lamarche ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Receptor ◽  
Signaling Pathway ◽  
Insulin Signaling ◽  
Insulin Response ◽  
Muscle Cells ◽  
Insulin Signaling Pathway ◽  
Akt Phosphorylation ◽  
Impaired Insulin

In type 2 diabetes (T2D), both muscle and liver are severely resistant to insulin action. Muscle insulin resistance accounts for more than 80% of the impairment in total body glucose disposal in T2D patients and is often characterized by an impaired insulin signaling. Mitsugumin 53 (MG53), a muscle-specific TRIM family protein initially identified as a key regulator of cell membrane repair machinery has been suggested to be a critical regulator of muscle insulin signaling pathway by acting as ubiquitin E3 ligase targeting both the insulin receptor and insulin receptor substrate 1 (IRS1). Here, we show using in vitro and in vivo approaches that MG53 is not a critical regulator of insulin signaling and glucose homeostasis. First, MG53 expression is not consistently regulated in skeletal muscle from various preclinical models of insulin resistance. Second, MG53 gene knock-down in muscle cells does not lead to impaired insulin response as measured by Akt phosphorylation on Serine 473 and glucose uptake. Third, recombinant human MG53 does not alter insulin response in both differentiated C2C12 and human skeletal muscle cells. Fourth, ectopic expression of MG53 in HEK293 cells lacking endogenous MG53 expression fails to alter insulin response as measured by Akt phosphorylation. Finally, both male and female mg53 -/- mice were not resistant to high fat induced obesity and glucose intolerance compared to wild-type mice. Taken together, these results strongly suggest that MG53 is not a critical regulator of insulin signaling pathway in skeletal muscle.

Defective insulin signaling in skeletal muscle of the hypertensive TG(mREN2)27 rat

2005 ◽  
Vol 288 (6) ◽  
pp. E1074-E1081 ◽  
Author(s):  
Julie A. Sloniger ◽  
Vitoon Saengsirisuwan ◽  
Cody J. Diehl ◽  
Betsy B. Dokken ◽  
Narissara Lailerd ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Angiotensin Ii ◽  
Insulin Receptor ◽  
Signaling Pathway ◽  
Glucose Transport ◽  
Insulin Signaling ◽  
Glycogen Synthase ◽  
Insulin Signaling Pathway ◽  
Whole Body

Essential hypertension is frequently associated with insulin resistance of skeletal muscle glucose transport, with a potential role of angiotensin II in the pathogenesis of both conditions. The male heterozygous TG(mREN2)27 rat harbors the mouse transgene for renin, exhibits local elevations in angiotensin II, and is an excellent model of both hypertension and insulin resistance. The present study was designed to investigate the potential cellular mechanisms for insulin resistance in this hypertensive animal model, including an assessment of elements of the insulin-signaling pathway. Compared with nontransgenic, normotensive Sprague-Dawley control rats, male heterozygous TG(mREN2)27 rats displayed elevated ( P < 0.05) fasting plasma insulin (74%), an exaggerated insulin response (108%) during an oral glucose tolerance test, and reduced whole body insulin sensitivity. TG(mREN2)27 rats also exhibited decreased insulin-mediated glucose transport and glycogen synthase activation in both the type IIb epitrochlearis (30 and 46%) and type I soleus (22 and 64%) muscles. Importantly, there were significant reductions (∼30–50%) in insulin stimulation of tyrosine phosphorylation of the insulin receptor β-subunit and insulin receptor substrate-1 (IRS-1), IRS-1 associated with the p85 subunit of phosphatidylinositol 3-kinase, Akt Ser473 phosphorylation, and Ser9 phosphorylation of glycogen synthase kinase-3β in epitrochlearis and soleus muscles of TG(mREN2)27 rats. Soleus muscle triglyceride concentration was 25% greater in the transgenic group compared with nontransgenic animals. Collectively, these data provide the first evidence that the insulin resistance of the hypertensive male heterozygous TG(mREN2)27 rat can be attributed to specific defects in the insulin-signaling pathway in skeletal muscle.

scholarly journals Intracellular pH Regulation of Skeletal Muscle in the Milieu of Insulin Signaling

Nutrients ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2910
Author(s):  
Dheeraj Kumar Posa ◽  
Shahid P. Baba
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Metabolic Syndrome ◽  
Signaling Pathway ◽  
Intracellular Ph ◽  
Cross Talk ◽  
Insulin Signaling ◽  
Insulin Signaling Pathway ◽  
Glycolytic Pathway ◽  
Insulin Responses

Type 2 diabetes (T2D), along with obesity, is one of the leading health problems in the world which causes other systemic diseases, such as cardiovascular diseases and kidney failure. Impairments in glycemic control and insulin resistance plays a pivotal role in the development of diabetes and its complications. Since skeletal muscle constitutes a significant tissue mass of the body, insulin resistance within the muscle is considered to initiate the onset of diet-induced metabolic syndrome. Insulin resistance is associated with impaired glucose uptake, resulting from defective post-receptor insulin responses, decreased glucose transport, impaired glucose phosphorylation, oxidation and glycogen synthesis in the muscle. Although defects in the insulin signaling pathway have been widely studied, the effects of cellular mechanisms activated during metabolic syndrome that cross-talk with insulin responses are not fully elucidated. Numerous reports suggest that pathways such as inflammation, lipid peroxidation products, acidosis and autophagy could cross-talk with insulin-signaling pathway and contribute to diminished insulin responses. Here, we review and discuss the literature about the defects in glycolytic pathway, shift in glucose utilization toward anaerobic glycolysis and change in intracellular pH [pH]i within the skeletal muscle and their contribution towards insulin resistance. We will discuss whether the derangements in pathways, which maintain [pH]i within the skeletal muscle, such as transporters (monocarboxylate transporters 1 and 4) and depletion of intracellular buffers, such as histidyl dipeptides, could lead to decrease in [pH]i and the onset of insulin resistance. Further we will discuss, whether the changes in [pH]i within the skeletal muscle of patients with T2D, could enhance the formation of protein aggregates and activate autophagy. Understanding the mechanisms by which changes in the glycolytic pathway and [pH]i within the muscle, contribute to insulin resistance might help explain the onset of obesity-linked metabolic syndrome. Finally, we will conclude whether correcting the pathways which maintain [pH]i within the skeletal muscle could, in turn, be effective to maintain or restore insulin responses during metabolic syndrome.

scholarly journals Blood Orange Juice Intake Modulates the Expression of miR-126–3p and let-7f-5p in PBMC of Overweight and Insulin Resistance Women

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 936-936
Author(s):  
Vinícius Cooper Capetini ◽  
Bruna Jardim Quintanilha ◽  
Geni Rodrigues Sampaio ◽  
Frederico Moraes Ferreira ◽  
Marcelo Rogero
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Signaling Pathway ◽  
Insulin Signaling ◽  
Orange Juice ◽  
Target Genes ◽  
Mononuclear Cells ◽  
Insulin Signaling Pathway ◽  
Model Assessment ◽  
Blood Orange

Abstract Objectives To investigate the effect of chronic blood orange juice intake on the microRNA profile in peripheral blood mononuclear cells (PBMC) of overweight and insulin resistance women. Methods Interventional and chronic study with women (n = 8) aged 18 to 40 years, diagnosed with overweight [body mass index (BMI) 25–29.9 kg/m2] and insulin resistance [homeostatic model assessment insulin resistance (HOMA-IR) index &gt;2,71]. For four weeks, the volunteers ingested 500 mL/day of blood orange juice (Moro variety), with blood samples collected at baseline and four weeks after the beginning of drink ingestion. Evaluation of the expression of 137 microRNAs in PBMC was performed by real-time polymerase chain reaction (PCR). Results Blood orange juice intake decreased the expression of miR-126-3p (p = 0.004) and let-7f-5p (p = 0.005) in PBMC. These microRNAs are involved in suppressing the synthesis of several proteins of the insulin signaling pathway. Insulin receptor substrates (IRS) 1 and 2 were identified as target genes of mir-126. Insulin-like growth factor 1 receptor (IGF1R), insulin receptor (INSR), IRS2, phosphatidylinositol-3-kinase interacting protein 1 (PIK3IP1), and protein kinase B/Akt 2 (AKT2) were identified as target genes of let-7f. Conclusions Blood orange juice, rich in vitamin C, flavonoids, and anthocyanins, downregulates the expression of microRNA involved in impairing the insulin signaling pathway. Funding Sources Food Research Center (FoRC), São Paulo Research Foundation (FAPESP)

Insulin secretion and signaling in response to dietary restriction and subsequent re-alimentation in cattle

2015 ◽  
Vol 47 (8) ◽  
pp. 344-354 ◽  
Author(s):  
Kate Keogh ◽  
David A. Kenny ◽  
Alan K. Kelly ◽  
Sinéad M. Waters
Keyword(s):  
Skeletal Muscle ◽  
Signaling Pathway ◽  
Dietary Restriction ◽  
Insulin Signaling ◽  
Compensatory Growth ◽  
Insulin Response ◽  
Insulin Signaling Pathway ◽  
Longissimus Dorsi ◽  
Period 2 ◽  
Ad Libitum

The objectives of this study were to examine systemic insulin response to a glucose tolerance test (GTT) and transcript abundance of genes of the insulin signaling pathway in skeletal muscle, during both dietary restriction and re-alimentation-induced compensatory growth. Holstein Friesian bulls were blocked to one of two groups: 1) restricted feed allowance for 125 days ( period 1) (RES, n = 15) followed by ad libitum feeding for 55 days ( period 2) or 2) ad libitum access to feed throughout (periods 1 and 2) (ADLIB, n = 15). On days 90 and 36 of periods 1 and 2, respectively, a GTT was performed. M. longissimus dorsi biopsies were harvested from all bulls on days 120 and 15 of periods 1 and 2, respectively, and RNA-Seq analysis was performed. RES displayed a lower growth rate during period 1 (RES: 0.6 kg/day, ADLIB: 1.9 kg/day; P < 0.001), subsequently gaining more during re-alimentation (RES: 2.5 kg/day, ADLIB: 1.4 kg/day; P < 0.001). Systemic insulin response to glucose administration was lower in RES in period 1 ( P < 0.001) with no difference observed during period 2. The insulin signaling pathway in M. longissimus dorsi was enriched ( P < 0.05) in response to dietary restriction but not during re-alimentation ( P > 0.05). Genes differentially expressed in the insulin signaling pathway suggested a greater sensitivity to insulin in skeletal muscle, with pleiotropic effects of insulin signaling interrupted during dietary restriction. Collectively, these results indicate increased sensitivity to glucose clearance and skeletal muscle insulin signaling during dietary restriction; however, no overall role for insulin was apparent in expressing compensatory growth.

scholarly journals Hypochlorous acid via peroxynitrite activates protein kinase Cθ and insulin resistance in adipocytes

2014 ◽  
Vol 54 (1) ◽  
pp. 25-37 ◽  
Author(s):  
Jun Zhou ◽  
Qilong Wang ◽  
Ye Ding ◽  
Ming-Hui Zou
Keyword(s):  
Insulin Resistance ◽  
Signaling Pathway ◽  
Insulin Signaling ◽  
High Fat Diet ◽  
Hypochlorous Acid ◽  
Insulin Signaling Pathway ◽  
Serine Phosphorylation ◽  
Impaired Insulin ◽  
Genetic Deletion

We recently reported that genetic deletion of myeloperoxidase (MPO) alleviates obesity-related insulin resistance in mice in vivo. How MPO impairs insulin sensitivity in adipocytes is poorly characterized. As hypochlorous acid (HOCl) is a principal oxidant product generated by MPO, we evaluated the effects of HOCl on insulin signaling in adipocytes differentiated from 3T3-L1 cells. Exposure of 3T3-L1 adipocytes to exogenous HOCl (200 μmol/l) attenuated insulin-stimulated 2-deoxyglucose uptake, GLUT4 translocation, and insulin signals, including tyrosine phosphorylation of insulin receptor substrate 1 (IRS1) and phosphorylation of Akt. Furthermore, treatment with HOCl induced phosphorylation of IRS1 at serine 307, inhibitor κB kinase (IKK), c-Jun NH2-terminal kinase (JNK), and phosphorylation of PKCθ (PKCθ). In addition, genetic and pharmacological inhibition of IKK and JNK abolished serine phosphorylation of IRS1 and impairment of insulin signaling by HOCl. Furthermore, knockdown of PKCθ using siRNA transfection suppressed phosphorylation of IKK and JNK and consequently attenuated the HOCl-impaired insulin signaling pathway. Moreover, activation of PKCθ by peroxynitrite was accompanied by increased phosphorylation of IKK, JNK, and IRS1-serine 307. In contrast, ONOO− inhibitors abolished HOCl-induced phosphorylation of PKCθ, IKK, JNK, and IRS1-serine 307, as well as insulin resistance. Finally, high-fat diet (HFD)-induced insulin resistance was associated with enhanced phosphorylation of PKCθ, IKK, JNK, and IRS1 at serine 307 in white adipose tissues from WT mice, all of which were not found in Mpo knockout mice fed HFDs. We conclude that HOCl impairs insulin signaling pathway by increasing ONOO− mediated phosphorylation of PKCθ, resulting in phosphorylation of IKK/JNK and consequent serine phosphorylation of IRS1 in adipocytes.

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