Chronic 17β-estradiol treatment improves skeletal muscle insulin signaling pathway components in insulin resistance associated with aging

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.

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

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00396.2004 ◽

2005 ◽

Vol 288 (6) ◽

pp. E1074-E1081 ◽

Cited By ~ 40

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.

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Resveratrol improves skeletal muscle insulin resistance through downregulating lncRNA NONMMUT044897.2

10.21203/rs.3.rs-315719/v1 ◽

2021 ◽

Author(s):

Zhihong Liu ◽

Zhimei Zhang ◽

Guangyao Song ◽

Xing Wang ◽

Hanying Xing ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Signaling Pathway ◽

Insulin Signaling ◽

High Fat Diet ◽

High Throughput Sequencing ◽

Insulin Signaling Pathway ◽

Cytokine Signaling ◽

Mice Model ◽

High Fat

Abstract Background: Long non-coding RNA (lncRNA) has proved to be crucial factors in the progression of insulin resistance (IR). Resveratrol (RSV) exhibits promising therapeutic potential for the IR. Nonetheless, whether RSV could influence the expression of lncRNAs and the interaction mechanisms in IR remain unclear.Methods: We conducted high-throughput sequencing to detect the lncRNAs and mRNAs expression signatures and the co-expression network of lncRNAs and mRNAs in skeletal muscle after a high-fat diet (HFD)-induced IR mice model with or without RSV treatment, including hierarchical clustering, gene enrichment and gene co-expression networks analysis. Highly differentially expressed lncRNAs were selected and validated by RT-qPCR. Finally, the biological functions of the selected lncRNAs were investigated by silencing expressing the target genes through lentivirus transfection in C2C12 mouse myotubes cells.Results: We revealed that 338 mRNAs and 629 lncRNAs whose expression in skeletal muscle after a high-fat diet (HFD)-induced IR mice model was reversed by RSV treatment. Gene Ontology and Kyoto encyclopedia of genes and genomes databases indicated that the differential expression mRNAs modulate the insulin signaling pathway. After validating randomly selected lncRNAs via RT-qPCR, we found that lncRNA (NONMMUT044897.2) and Suppressor of Cytokine Signaling 1 (SOCS1) were up-regulated in the HFD group, and reversed by RSV treatment. Additionally, NONMMUT044897.2 was validated to function as a ceRNA of microRNA (miR)-7051-5p and SOCS1 was confirmed as a target for miR‑7051-5p. We further performed lentivirus transfection to knockdown NONMMUT044897.2 in vitro and found that NONMMUT044897.2 silence inactivated SOCS1 and promoted the insulin signaling pathway. Importantly, RSV could mimic the effects of silencing NONMMUT044897.2.Conclusion: Our study revealed that resveratrol improves skeletal muscle IR might be via regulation of NONMUT044897.2.

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

10.1101/2020.12.24.424288 ◽

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.

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

PLoS ONE ◽

10.1371/journal.pone.0245179 ◽

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.

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