The TORC1/P70S6K and TORC1/4EBP1 signaling pathways have a stronger contribution on skeletal muscle growth than MAPK/ERK in an early vertebrate: Differential involvement of the IGF system and atrogenes

Fuentes, Eduardo N.; Einarsdóttir, Ingibjörg Eir; Paredes, Rodolfo; Hidalgo, Christian; Valdés, Juan Antonio; Björnsson, Björn Thrándur; Molina, Alfredo

doi:10.1016/j.ygcen.2014.10.012

Cited by 26 publications

(13 citation statements)

References 42 publications

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“…Therefore, altered RBM20 level is a key for insulin or thyroid hormone-induced titin splicing. In addition, activation of mTOR results in phosphorylation of p70S6K1 and translational repressor 4E-BP1, which phosphorylation of these two proteins promote protein synthesis [44]. With mTOR inhibition and down-regulation of p70S6K and 4E-BP1, our data further depicted an essential role of RBM20 expression through activation of downstream effectors of mTOR signalling in the regulation of titin splicing (depicted in Fig.…”

Section: Discussionmentioning

confidence: 52%

Insulin regulates titin pre-mRNA splicing through the PI3K-Akt-mTOR kinase axis in a RBM20-dependent manner

Zhu

Yin

Tan

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Titin, a giant sarcomeric protein, is largely responsible for the diastolic properties of the heart. It has two major isoforms, N2B and N2BA due to pre-mRNA splicing regulated mainly by a splicing factor RNA binding motif 20 (RBM20). Mis-splicing of titin pre-mRNA in response to external stimuli may lead to altered ratio of N2B to N2BA, and thus, impaired cardiac contractile function. However, little is known about titin alternative splicing in response to external stimuli. Here, we reported the detailed mechanisms of titin alternative splicing in response to insulin. Insulin treatment in cultured neonatal rat cardiomyocytes (NRCMs) activated the PI3K-Akt-mTOR Kinase axis, leading to increased N2B expression in the presence of RBM20, but not in NRCMs in the absence of RBM20. By inhibiting this kinase axis with inhibitors, decreased N2B isoform was observed in NRCMs and also in diabetic rat model treated with streptozotocin, but not in NRCMs and diabetic rats in the absence of RBM20. In addition to the alteration of titin isoform ratios in response to insulin, we found that RBM20 expression was increased in NRCMs with insulin treatment, suggesting that RBM20 levels were also regulated by insulin-induced kinase axis. Further, knockdown of p70S6K1 with siRNA reduced both RBM20 and N2B levels, while knockdown of 4E-BP1 elevated expression levels of RBM20 and N2B. These findings reveal a major signal transduction pathway for insulin-induced titin alternative splicing, and place RBM20 in a central position in the pathway, which is consistent with the reputed role of RBM20 in titin alternative splicing. Findings from this study shed light on gene therapeutic strategies at the molecular level by correction of pre-mRNA mis-splicing.

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Section: Discussionmentioning

confidence: 52%

Insulin regulates titin pre-mRNA splicing through the PI3K-Akt-mTOR kinase axis in a RBM20-dependent manner

Zhu

Yin

Tan

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…Several extracellular growth factors and intracellular signaling pathways are involved in the growth and differentiation of skeletal muscle. The role of MEK/ERK signaling pathway in skeletal muscle wasting is controversial (10,33). We found that ERK phosphorylation was enhanced in wasting skeletal muscle in a murine model of cancer cachexia.…”

Section: Discussionmentioning

confidence: 92%

“…Activation of MEK/ERK pathway was detected in the wasted muscle tissue of in vivo cancer cachexia model and in the differentiated myotubes of in vitro myofiber atrophy model (10)(11)(12)(13). Progressive skeletal muscle wasting was mainly mediated via ubiquitin-proteasome pathway (14).…”

Section: Introductionmentioning

confidence: 99%

Selumetinib Attenuates Skeletal Muscle Wasting in Murine Cachexia Model through ERK Inhibition and AKT Activation

Yang

Huo

Han

et al. 2017

Molecular Cancer Therapeutics

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Cancer cachexia is a multifactorial syndrome affecting the skeletal muscle. Previous clinical trials showed that treatment with MEK inhibitor selumetinib resulted in skeletal muscle anabolism. However, it is conflicting that MAPK/ERK pathway controls the mass of the skeletal muscle. The current study investigated the therapeutic effect and mechanisms of selumetinib in amelioration of cancer cachexia. The classical cancer cachexia model was established via transplantation of CT26 colon adenocarcinoma cells into BALB/c mice. The effect of selumetinib on body weight, tumor growth, skeletal muscle, food intake, serum proinflammatory cytokines, E3 ligases, and MEK/ERK-related pathways was analyzed. Two independent experiments showed that 30 mg/kg/d selumetinib prevented the loss of body weight in murine cachexia mice. Muscle wasting was attenuated and the expression of E3 ligases, MuRF1 and Fbx32, was inhibited following selumetinib treatment of the gastrocnemius muscle. Furthermore, selumetinib efficiently reduced tumor burden without influencing the cancer cell proliferation, cumulative food intake, and serum cytokines. These results indicated that the role of selumetinib in attenuating muscle wasting was independent of cancer burden. Detailed analysis of the mechanism revealed AKT and mTOR were activated, while ERK, FoxO3a, and GSK3b were inhibited in the selumetinib -treated cachexia group. These indicated that selumetinib effectively prevented skeletal muscle wasting in cancer cachexia model through ERK inhibition and AKT activation in gastrocnemius muscle via cross-inhibition. The study not only elucidated the mechanism of MEK/ERK inhibition in skeletal muscle anabolism, but also validated selumetinib therapy as an effective intervention against cancer cachexia.

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“…Ten images were randomly captured on each coverslip (replicate sample). The diameter of each myotube ( 6 – 10 ) in each image was measured and used to calculate the mean myotube diameter for each sample replicate ( n =5).…”

Section: Methodsmentioning

confidence: 99%

“…It is noteworthy that the protein level in skeletal muscle is dependent on mammalian target of rapamycin (mTOR) and forkhead box O (FoxO) family. mTOR plays a critical role in promoting the protein synthesis of skeletal muscle through its downstream S6, P70S6K1, 4E-BP1, and eIF4E ( 6 – 8 ), while FoxO1 and FoxO3a induce the degradation of protein by regulating expression of MuRF1 and MAFbx ( 9 ).…”

Section: Introductionmentioning

confidence: 99%

Succinate promotes skeletal muscle protein synthesis via Erk1/2 signaling pathway

Yuan

et al. 2017

Molecular Medicine Reports

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It is well known that endurance training is effective to attenuate skeletal muscle atrophy. Succinate is a typical TCA metabolite, of which exercise could dramatically increase the content. The present study aimed to investigate the effect of succinate on protein synthesis in skeletal muscle, and try to delineate the underlying mechanism. The in vitro study revealed that succinate dose-dependently increased protein synthesis in C2C12 myotube along with the enhancement of phosphorylation levels of AKT Serine/Threonine Kinase 1(Akt), mammalian target of rapamycin, S6, eukaryotic translation initiation factor 4E, 4E binding protein 1 and forkhead box O (FoxO) 3a. Furthermore, it was demonstrated that 20 mM succinate markedly increased [Ca2+]i. Then, the phospho-extracellular regulated kinase (Erk), -Akt level and the crosstalk between Erk and Akt were elevated in response to succinate. Notably, the Erk antagonist (U0126) or mTOR inhibitor (rapamycin) abolished the effect of succinate on protein synthesis. The in vivo study verified that succinate dose-dependently increased the protein synthesis, in addition to phosphorylation levels of Erk, Akt and FoxO3a in gastrocnemius muscle. In summary, these findings demonstrated that succinate promoted skeletal muscle protein deposition via Erk/Akt signaling pathway.

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The TORC1/P70S6K and TORC1/4EBP1 signaling pathways have a stronger contribution on skeletal muscle growth than MAPK/ERK in an early vertebrate: Differential involvement of the IGF system and atrogenes

Cited by 26 publications

References 42 publications

Insulin regulates titin pre-mRNA splicing through the PI3K-Akt-mTOR kinase axis in a RBM20-dependent manner

Insulin regulates titin pre-mRNA splicing through the PI3K-Akt-mTOR kinase axis in a RBM20-dependent manner

Selumetinib Attenuates Skeletal Muscle Wasting in Murine Cachexia Model through ERK Inhibition and AKT Activation

Succinate promotes skeletal muscle protein synthesis via Erk1/2 signaling pathway

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