Mechanisms by which smoothelin-like protein 1 reverses insulin resistance in myotubules and mice

Tamás, István; Major, E; Horváth, Dorottya; Keller, Ilka; Ungvari, Adam; Haystead, Timothy A.J.; MacDonald, Justin A.; Lontay, Beáta

doi:10.1016/j.mce.2022.111663

Cited by 4 publications

(10 citation statements)

References 40 publications

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“…A recent in vitro study reported an insulin-sensitizing role for SMTNL1 with its overexpression in C2C12 myotubes, mainly by the activation of Akt and induction of glucose transporter (Glut-4) expression (Tamas et al 2022). The overexpression study showed that in the presence of progesterone, SMTNL1 could downregulate novel PKCε as well as JNK1 and relieve the inhibitory phosphorylation of insulin receptor substrate 1 at Ser318 and Ser307.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the deletion of SMTNL1 in young female mice promoted the switching of skeletal muscle from an oxidative to a glycolytic phenotype akin to what was observed in pregnant animals (Lontay et al 2015). SMTNL1 can influence elements of thyroid hormone signaling, insulin signaling and glucose metabolism in C2C12 myotubes and potentially prevents hyperthyroidism-induced changes in skeletal muscle (Tamas et al 2022; Major et al 2021). However, the role of Smtnl1 in the regulation of energy balance is largely unknown.…”

Section: Introductionmentioning

confidence: 99%

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Sex dimorphism in the aged metabolic phenotype of smoothelin-like 1 (SMTNL1) deficient mice

Murali,

Alabi,

Chelikani

et al. 2023

Preprint

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Smoothelin-like 1 (SMTNL1) is expressed in smooth and skeletal muscle tissues as well as a variety of steroid hormone-sensitive tissues. SMTNL1 can play a sex-dependent regulatory role in skeletal muscle metabolism in mice. Previous studies have documented appreciable changes in muscle morphology and metabolic function of young male mice with genetic deletion of Smtnl1. SMTNL1 can also impact the energy metabolism and insulin sensitivity of female mice during pregnancy. Therefore, we investigated the metabolic outcome of global SMTNL1 knockout (KO) in male and female mice with advancing age using a comprehensive lab animal monitoring system (CLAMS). With ageing, body weight gain was markedly higher with a concomitant increase in whole body adiposity as well as specific white adipose depots in the absence of SMTNL1. Moreover, this genotypic difference in whole body adiposity was greater in the female cohort. The deletion of SMTNL1 was also associated with delayed satiety in mice fed a high fat diet, which was more pronounced in the female mice. A significant genotypic difference was also revealed for the metabolic energy balance in 12 month old animals of both sexes. The KO animals were metabolically less efficient and displayed a preference for carbohydrate catabolism. However, reduced glucose tolerance was observed only in the female group with the deletion of SMTNL1. Taken together, the current findings establish a novel role for SMTNL1 in modulating adiposity and energy metabolism with ageing in a sex dimorphic way.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sex dimorphism in the aged metabolic phenotype of smoothelin-like 1 (SMTNL1) deficient mice

Murali,

Alabi,

Chelikani

et al. 2023

Preprint

Self Cite

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“…SMTNL1 is a potent regulator of insulin signaling, as shown in an in vitro insulin-resistant C2C12 rodent cell line skeletal muscle model. In mouse and differentiated skeletal muscle cell culture models of insulin resistance, SMTNL1 can attenuate the effects of altered IRS-1 serine phosphorylation induced by the over-activation of Ser/Thr protein kinases (14,15). By reducing the expression of novel type PKCϵ (nPKCϵ), SMTNL1 can downregulate the activity of ERK 1/2 MAPK, resulting in decreased IRS-1 Ser612 phosphorylation, which was boosted by in vitro hyperinsulinemichyperglycemic conditions (14,16).…”

Section: Introductionmentioning

confidence: 99%

“…In mouse and differentiated skeletal muscle cell culture models of insulin resistance, SMTNL1 can attenuate the effects of altered IRS-1 serine phosphorylation induced by the over-activation of Ser/Thr protein kinases (14,15). By reducing the expression of novel type PKCϵ (nPKCϵ), SMTNL1 can downregulate the activity of ERK 1/2 MAPK, resulting in decreased IRS-1 Ser612 phosphorylation, which was boosted by in vitro hyperinsulinemichyperglycemic conditions (14,16). Thus, SMTNL1 prevents the dissociation of the IRS-1-PI3K-Akt-mTOR pathway and acts as an insulin-sensitizing agent in our in vitro rodent model.…”

Section: Introductionmentioning

confidence: 99%

“…Thus, SMTNL1 prevents the dissociation of the IRS-1-PI3K-Akt-mTOR pathway and acts as an insulin-sensitizing agent in our in vitro rodent model. Moreover, SMTNL1 can induce GLUT4-mediated glucose uptake in C2C12 cells (14). In Smtnl1 -/mice, fitness is reduced, including reduced litter size, elongated times between pregnancies, and glucose intolerance, especially in pregnant animals (15).…”

Section: Introductionmentioning

confidence: 99%

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Smoothelin-like protein 1 promotes insulin sensitivity and modulates the contractile properties of endometrial epithelial cells with insulin resistance

Keller,

Ungvári,

Kinter

et al. 2024

Front. Endocrinol.

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IntroductionThe incidence of infertility is significantly higher in women with diseases linked to impaired glucose homeostasis, such as insulin resistance. Defective glucose metabolism interferes with fertilization; however, the molecular mechanism underlying this interference is unclear. Smoothelin-like protein 1 (SMTNL1) was isolated from muscle and steroid hormone-responsive tissues and regulates the contractile functions of various cell types through the inhibition of myosin phosphatase (MP) holoenzyme. In addition, SMTNL-1 after phosphorylation at Ser301 by protein kinase A translocates to the nucleus and functions as a transcriptional co-activator of the progesterone receptor-B. SMTNL1 null mice exhibit reduced reproductive fitness and are more prone to type 2 diabetes mellitus. However, the role of SMTNL1 in endometrial epithelial cells is not known.MethodsThe effect of SMTNL1 overexpression was investigated in pregnancy and in gestational diabetic endometrial epithelial cell models by immunofluorescent staining, cell migration, and semi quantitative Western blot analysis and glucose uptake assay.ResultsWe show that SMTNL1 promotes the differentiation of endometrial epithelial cells in a progesterone-dependent manner to attenuate insulin resistance. Furthermore, SMTNL1 hampers the migration capacity of epithelial cells in a gestational diabetes model by inhibiting the expression of MYPT1, the regulatory subunit of MP, and the activity of the holoenzyme, resulting in increased phosphorylation of the 20 kDa regulatory myosin light chain. SMTNL1 also acts as an insulin-sensitizing agent by increasing the gene expression of PP2A and DUPS9 protein phosphatases, resulting in decreased ERK1/2 activity and, hence, decreasing the phosphorylation of IRS-1 at Ser612 under gestational diabetes conditions.ConclusionSMTNL1 may have therapeutic relevance to the progesterone-dependent inhibition of endometrial epithelial cell migration under hyperglycemic conditions and insulin sensitivity in the endometrium in gestational diabetes or other metabolic disorders.

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Maternal immune cell gene expression associates with maternal gut microbiome, milk composition and infant gut microbiome

Gurung,

Mulakala,

Schlegel

et al. 2024

Clinical Nutrition ESPEN

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Mechanisms by which smoothelin-like protein 1 reverses insulin resistance in myotubules and mice

Cited by 4 publications

References 40 publications

Sex dimorphism in the aged metabolic phenotype of smoothelin-like 1 (SMTNL1) deficient mice

Sex dimorphism in the aged metabolic phenotype of smoothelin-like 1 (SMTNL1) deficient mice

Smoothelin-like protein 1 promotes insulin sensitivity and modulates the contractile properties of endometrial epithelial cells with insulin resistance

Maternal immune cell gene expression associates with maternal gut microbiome, milk composition and infant gut microbiome

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