The Translation Regulatory Subunit eIF3f Controls the Kinase-Dependent mTOR Signaling Required for Muscle Differentiation and Hypertrophy in Mouse

The mTORC1 pathway is required for both the terminal muscle differentiation and hypertrophy by controlling the mammalian translational machinery via phosphorylation of S6K1 and 4E-BP1. mTOR and S6K1 are connected by interacting with the eIF3 initiation complex. The regulatory subunit eIF3f plays a major role in muscle hypertrophy and is a key target that accounts for MAFbx function during atrophy. Here we present evidence that in MAFbx-induced atrophy the degradation of eIF3f suppresses S6K1 activation by mTOR, whereas an eIF3f mutant insensitive to MAFbx polyubiquitination maintained persistent phosphorylation of S6K1 and rpS6. During terminal muscle differentiation a conserved TOS motif in eIF3f connects mTOR/raptor complex, which phosphorylates S6K1 and regulates downstream effectors of mTOR and Cap-dependent translation initiation. Thus eIF3f plays a major role for proper activity of mTORC1 to regulate skeletal muscle size

Appetite for destruction: the inhibition of glycolysis as a therapy for tuberous sclerosis complex-related tumors

The elevated metabolic requirements of cancer cells reflect their rapid growth and proliferation and are met through mutations in oncogenes and tumor suppressor genes that reprogram cellular processes. For example, in tuberous sclerosis complex (TSC)-related tumors, the loss of TSC1/2 function causes constitutive mTORC1 activity, which stimulates glycolysis, resulting in glucose addiction in vitro. In research published in Cell and Bioscience, Jiang and colleagues show that pharmacological restriction of glucose metabolism decreases tumor progression in a TSC xenograft model

Estradiol and mTORC2 cooperate to enhance prostaglandin biosynthesis and tumorigenesis in TSC2-deficient LAM cells

Lymphangioleiomyomatosis (LAM) is a progressive neoplastic disorder that leads to lung destruction and respiratory failure primarily in women. LAM is typically caused by tuberous sclerosis complex 2 (TSC2) mutations resulting in mTORC1 activation in proliferative smooth muscle–like cells in the lung. The female predominance of LAM suggests that estradiol contributes to disease development. Metabolomic profiling identified an estradiol-enhanced prostaglandin biosynthesis signature in Tsc2-deficient (TSC−) cells, both in vitro and in vivo. Estradiol increased the expression of cyclooxygenase-2 (COX-2), a rate-limiting enzyme in prostaglandin biosynthesis, which was also increased at baseline in TSC-deficient cells and was not affected by rapamycin treatment. However, both Torin 1 treatment and Rictor knockdown led to reduced COX-2 expression and phospho-Akt-S473. Prostaglandin production was also increased in TSC-deficient cells. In preclinical models, both Celecoxib and aspirin reduced tumor development. LAM patients had significantly higher serum prostaglandin levels than healthy women. 15-epi-lipoxin-A4 was identified in exhaled breath condensate from LAM subjects and was increased by aspirin treatment, indicative of functional COX-2 expression in the LAM airway. In vitro, 15-epi-lipoxin-A4 reduced the proliferation of LAM patient–derived cells in a dose-dependent manner. Targeting COX-2 and prostaglandin pathways may have therapeutic value in LAM and TSC-related diseases, and possibly in other conditions associated with mTOR hyperactivation

Inhibition of Atrogin-1/MAFbx Mediated MyoD Proteolysis Prevents Skeletal Muscle Atrophy In Vivo

Ubiquitin ligase Atrogin1/Muscle Atrophy F-box (MAFbx) up-regulation is required for skeletal muscle atrophy but substrates and function during the atrophic process are poorly known. The transcription factor MyoD controls myogenic stem cell function and differentiation, and seems necessary to maintain the differentiated phenotype of adult fast skeletal muscle fibres. We previously showed that MAFbx mediates MyoD proteolysis in vitro. Here we present evidence that MAFbx targets MyoD for degradation in several models of skeletal muscle atrophy. In cultured myotubes undergoing atrophy, MAFbx expression increases, leading to a cytoplasmic-nuclear shuttling of MAFbx and a selective suppression of MyoD. Conversely, transfection of myotubes with sh-RNA-mediated MAFbx gene silencing (shRNAi) inhibited MyoD proteolysis linked to atrophy. Furthermore, overexpression of a mutant MyoDK133R lacking MAFbx-mediated ubiquitination prevents atrophy of mouse primary myotubes and skeletal muscle fibres in vivo. Regarding the complex role of MyoD in adult skeletal muscle plasticity and homeostasis, its rapid suppression by MAFbx seems to be a major event leading to skeletal muscle wasting. Our results point out MyoD as the second MAFbx skeletal muscle target by which powerful therapies could be developed

Rôle pivot du facteur d'initiation eIF3f dans l'antagonisme atrophie/hypertrophie du muscle squelettique

Le contrôle de la masse musculaire est déterminé par un équilibre entre les processus anaboliques et cataboliques. L'hypertrophie musculaire se caractérise par une augmentation de la synthèse protéique par activation de la voie IGF1/Akt/mTORC1. L'atrophie est le résultat d'une augmentation de la dégradation des protéines, dont le système ubiquitine-protéasome joue un rôle majeur. MAFbx est une E3 ubiquitine ligase dont l'expression est fortement augmentée lors de l'induction de l'atrophie. Les substrats ciblés par MAFbx restent à déterminer. Nous avons identifié le facteur d'initiation eIF3f comme cible du complexe SCFMAFbx lors de l'atrophie. MAFbx induit la poly-ubiquitination sur six residus lysines d'eIF3f conduisant ainsi sa dégradation par le protéasome. Nous montrons le rôle clé d'eIF3f dans l'induction de l'hypertrophie, caractérisée par une augmentation de l'activité de la voie mTORC1. De plus, la sur-expression d'un mutant d'eIF3f résistant à l'ubiquitination est associée à une protection effective contre l'atrophie. eIF3f apparaît être une cible clé de la fonction de MAFbx lors de l'atrophie du muscle et joue un rôle majeur dans l'hypertrophieSkeletal muscle (SM) mass depends upon a dynamic balance between anabolic and catabolic processes. SM hypertrophy is characterized by increased protein synthesis mainly by activation of the IGF1/Akt/mTORC1 pathway. SM atrophy is the results of increased protein breakdown, in which the ubiquitin-proteasome pathway plays a major role. MAFbx is an E3 ligase whose expression is upregulated during muscle atrophy. However the precise function of the SCFMAFbx ubiquitin-ligase in muscle wasting remains unknown. Here, we characterized eIF3f as a target of the SCFMAFbx complex during muscle atrophy. MAFbx induces the poly-ubiquitination of eIF3f in six lyisine residues leading to its proteasomal degradation. We demonstrate that eIF3f plays a key role in hypertrophic by increasing the activity of the mTORC1 pathway. In addition, the overexpression of an eIF3f mutant resistant to poly-ubiquitination is associated with protection against muscle atrophy. Taken together, the specific targeting of eIF3f by MAFbx may account for the decreased protein synthesis observed in atrophy, and eIF3f plays an important role as a mediator of SM hypertrophyMONTPELLIER-BU Sciences (341722106) / SudocSudocFranceF

Efecto de la Hipoxia Intermitente Crónica sobre la Nitración y la Fosforilación de las Kinasas reguladas por señales extracelulares en la Corteza Primaria del Cerebro de la Rata

La hipoxia intermitente crónica (HIC) emerge como un problema de salud pública de alta prevalencia y constituyeuna de las principales causas de las alteraciones sustanciales de tipo neuroconductual y cardiovasculares en pacientesadultos y en desarrollo. En el presente trabajo evaluamos el efecto que ejerce la HIC sobre la señalización de laskinasas reguladas por señales extracelulares (ERK 1/2) en la corteza cerebral de la rata. Demostramos, por primeravez, que la HIC induce nitración y activación de las ERK 1/2 en la corteza cerebral de la rata. El pretratamiento invivo con candesartan inhibió la nitración y la fosforilación de las ERK1/2 inducidas por la HIC en la corteza cerebral.Nuestros hallazgos apuntan hacia un papel de la nitración en la vía de señalización de las MAPK cerebrales durante laHIC, e indican que estos efectos están mediados a través de la estimulación del receptor AT1 de la angiotensina II

Central role of AMPK in the regulation of skeletal muscle protein turnover

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