bims-tubesc Biomed News
on Molecular mechanisms in tuberous sclerosis
Issue of 2021‒10‒24
fourteen papers selected by
Marti Cadena Sandoval
metabolic-signalling.eu
  1. Renal Cell Carcinoma in Tuberous Sclerosis Complex.
  2. Profile of Autism Spectrum Disorder in Tuberous Sclerosis Complex: Results from a longitudinal, prospective, multi-site study.
  3. Editorial: Tuberous Sclerosis Complex - Diagnosis and Management.
  4. mTORC1-induced retinal progenitor cell overproliferation leads to accelerated mitotic aging and degeneration of descendent Müller glia.
  5. Health-related quality of life in children and adolescents with tuberous sclerosis complex and their caregivers: A multicentre cohort study from Germany.
  6. mTORC1 promotes malignant large cell/anaplastic histology and is a targetable vulnerability in SHH-TP53 mutant medulloblastomas.
  7. Pib2 as an Emerging Master Regulator of Yeast TORC1.
  8. The SZT2 Interactome Unravels New Functions of the KICSTOR Complex.
  9. AKAP13 couples GPCR signaling to mTORC1 inhibition.
  10. Activation of mTORC1 by Free Fatty Acids Suppresses LAMP2 and Autophagy Function via ER Stress in Alcohol-Related Liver Disease.
  11. REDD1 deletion attenuates cancer cachexia in mice.
  12. AZD2014, a dual mTOR inhibitor, attenuates cardiac hypertrophy in vitro and in vivo.
  13. Loss of REDD1 prevents chemotherapy-induced muscle atrophy and weakness in mice.
  14. mTOR-related synaptic pathology causes autism spectrum disorder-associated functional hyperconnectivity.
  1. Genes (Basel). 2021 Oct 08. pii: 1585. [Epub ahead of print]12(10):
    Renal Cell Carcinoma in Tuberous Sclerosis Complex.
    Elizabeth P Henske, Kristine M Cornejo, Chin-Lee Wu.
      Tuberous sclerosis complex (TSC) is an autosomal dominant disorder in which renal manifestations are prominent. There are three major renal lesions in TSC: angiomyolipomas, cysts, and renal cell carcinoma (RCC). Major recent advances have revolutionized our understanding of TSC-associated RCC, including two series that together include more than 100 TSC-RCC cases, demonstrating a mean age at onset of about 36 years, tumors in children as young as 7, and a striking 2:1 female predominance. These series also provide the first detailed understanding of the pathologic features of these distinctive tumors, which include chromophobe-like features and eosinophilia, with some of the tumors unclassified. This pathologic heterogeneity is distinctive and reminiscent of the pathologic heterogeneity in Birt-Hogg-Dube-associated RCC, which also includes chromophobe-like tumors. Additional advances include the identification of sporadic counterpart tumors that carry somatic TSC1/TSC2/mTOR mutations. These include unclassified eosinophilic tumors, eosinophilic solid cystic RCC (ESC-RCC), and RCC with leiomyomatous stroma (RCCLMS). A variety of epithelial renal neoplasms have been identified both in patients with tuberous sclerosis complex (TSC) and in the nonsyndromic setting associated with somatic mutations in the TSC1 and TSC2 genes. Interestingly, whether tumors are related to a germline or somatic TSC1/2 mutation, these tumors often display similar morphologic and immunophenotypic features. Finally, recent work has identified molecular links between TSC and BHD-associated tumors, involving the TFEB/TFE3 transcription factors.
    Keywords:  RCC with leiomyomatous stroma; TSC1; TSC2; chromophobe RCC; eosinophilic solid cystic RCC; hybrid oncocytic chromophobe tumor; renal cell carcinoma; tuberous sclerosis complex
    DOI:  https://doi.org/10.3390/genes12101585
  2. Ann Neurol. 2021 Oct 20.
    Profile of Autism Spectrum Disorder in Tuberous Sclerosis Complex: Results from a longitudinal, prospective, multi-site study.
    TACERN Study Group
      OBJECTIVE: Tuberous Sclerosis Complex (TSC) is highly associated with autism spectrum disorder (ASD). Objectives of the study were to characterize autistic features in young children with TSC.METHODS: Participants included 138 children followed from ages 3 to 36 months with TSC from the Tuberous Sclerosis Complex Autism Center of Excellence Research Network (TACERN), a multicenter, prospective observational study aimed at understanding the underlying mechanisms of ASD in TSC. Developmental and autism-specific assessments were administered, and a clinical diagnosis of ASD was determined for all participants at 36 months. Further analyses were performed on 117 participants with valid autism assessments based on nonverbal mental age greater than 15 months.
    RESULTS: Prevalence of clinical diagnosis of ASD at 36 months was 25%. Nearly all autistic behaviors on the Autism Diagnostic Observation Schedule-2 (ADOS-2) and Autism Diagnostic Interview-Revised (ADI-R) were more prevalent in children diagnosed with ASD; however, autism-specific behaviors were also observed in children without ASD. Overall quality of social overtures, facial expressions, and abnormal repetitive interests and behaviors were characteristics most likely to distinguish children with ASD from those without an ASD diagnosis. Participants meeting ADOS-2 criteria but not a clinical ASD diagnosis exhibited intermediate developmental and ADOS-2 scores compared to individuals with and without ASD.
    INTERPRETATION: ASD is highly prevalent in TSC, and many additional individuals with TSC exhibit a broad range of sub-threshold autistic behaviors. Our findings reveal a broader autism phenotype that can be identified in young children with TSC, which provides opportunity for early targeted treatments. This article is protected by copyright. All rights reserved.
    Keywords:  TSC-Associated Neuropsychiatric Disorder (TAND); Tuberous Sclerosis Complex; autism spectrum disorder
    DOI:  https://doi.org/10.1002/ana.26249
  3. Front Neurol. 2021 ;12 755868
    Editorial: Tuberous Sclerosis Complex - Diagnosis and Management.
    Sergiusz Jozwiak, Paolo Curatolo.
      
    Keywords:  diagnosis; epilepsy; genetics; treatment; tuberous sclerosis complex (TSC)
    DOI:  https://doi.org/10.3389/fneur.2021.755868
  4. Elife. 2021 Oct 22. pii: e70079. [Epub ahead of print]10
    mTORC1-induced retinal progenitor cell overproliferation leads to accelerated mitotic aging and degeneration of descendent Müller glia.
    Soyeon Lim, You-Joung Kim, Sooyeon Park, Ji-Heon Choi, Younghoon Sung, Katsuhiko Nishimori, Zybmek Kozmik, Han-Woong Lee, Jin Woo Kim.
      Retinal progenitor cells (RPCs) divide in limited numbers to generate the cells comprising vertebrate retina. The molecular mechanism that leads RPC to the division limit, however, remains elusive. Here, we find that the hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) in an RPC subset by deletion of tuberous sclerosis complex 1 (Tsc1) makes the RPCs arrive at the division limit precociously and produce Müller glia (MG) that degenerate from senescence-associated cell death. We further show the hyperproliferation of Tsc1-deficient RPCs and the degeneration of MG in the mouse retina disappear by concomitant deletion of hypoxia-induced factor 1-a (Hif1a), which induces glycolytic gene expression to support mTORC1-induced RPC proliferation. Collectively, our results suggest that, by having mTORC1 constitutively active, an RPC divides and exhausts mitotic capacity faster than neighboring RPCs, and thus produces retinal cells that degenerate with aging-related changes.
    Keywords:  developmental biology; mouse
    DOI:  https://doi.org/10.7554/eLife.70079
  5. Eur J Paediatr Neurol. 2021 Oct 07. pii: S1090-3798(21)00185-9. [Epub ahead of print]35 111-122
    Health-related quality of life in children and adolescents with tuberous sclerosis complex and their caregivers: A multicentre cohort study from Germany.
    Laurent M Willems, Susanne Schubert-Bast, Janina Grau, Christoph Hertzberg, Gerhard Kurlemann, Adelheid Wiemer-Kruel, Thomas Bast, Astrid Bertsche, Ulrich Bettendorf, Barbara Fiedler, Andreas Hahn, Hans Hartmann, Frauke Hornemann, Ilka Immisch, Julia Jacobs, Matthias Kieslich, Karl Martin Klein, Kerstin A Klotz, Gerhard Kluger, Markus Knuf, Thomas Mayer, Klaus Marquard, Sascha Meyer, Hiltrud Muhle, Karen Müller-Schlüter, Anna H Noda, Susanne Ruf, Matthias Sauter, Jan-Ulrich Schlump, Steffen Syrbe, Charlotte Thiels, Regina Trollmann, Bernd Wilken, Johann Philipp Zöllner, Felix Rosenow, Adam Strzelczyk.
      OBJECTIVE: This study aimed to measure health-related quality of life (HRQOL) in children and adolescents with tuberous sclerosis complex (TSC) and quality of life (QOL) and depressive symptoms among caregivers.METHODS: Adequate metrics were used to assess HRQOL in children and adolescents with TSC (4-18 years, KINDLR) as well as QOL (EQ-5D) and symptoms of depression (BDI-II) among caregivers. Predictors for reduced HRQOL and depressive symptoms were identified by variance analysis, ordinal regression, and bivariate correlation.
    RESULTS: The mean HRQOL score was 67.9 ± 12.7, and significantly lower values were associated with increasing age, attending special needs education, TSC-associated psychiatric symptoms, and drug-related adverse events. The mean QOL of caregivers was 85.4 ± 15.7, and caregiver's sex, TSC mutation locus, familial TSC clustering, special needs education, degree of disability, care dependency, presence of TSC-associated psychiatric symptoms, and TSC severity were significant predictors of lower QOL. Depressive symptoms were identified in 45.7% of caregivers, associated with female sex of the caregiver, familial TSC clustering, special needs education, and presence of TSC-associated psychiatric symptoms of the child. Multivariate regression analysis revealed adolescence and drug-related adverse events as significant predictors for lower HRQOL in TSC children, and TSC2 variants predicted lower QOL and depressive symptoms in caregivers.
    CONCLUSION: Compared with other chronic diseases, such as headache, diabetes or obesity, children with TSC have significantly lower HRQOL, which further decreases during adolescence. A decreased HRQOL of patients correlates with a lower QOL and increased symptoms of depression of their caregivers. These results may improve the comprehensive therapy and care of children and adolescents with TSC and their families and caregivers.
    TRIAL REGISTRATION: DRKS, DRKS00016045. Registered 01 March 2019, http://www.drks.de/DRKS00016045.
    Keywords:  Angiomyolipoma; Depression; Epilepsy; Seizure; TSC
    DOI:  https://doi.org/10.1016/j.ejpn.2021.10.003
  6. JCI Insight. 2021 Oct 21. pii: e153462. [Epub ahead of print]
    mTORC1 promotes malignant large cell/anaplastic histology and is a targetable vulnerability in SHH-TP53 mutant medulloblastomas.
    Valentina Conti, Manuela Cominelli, Valentina Pieri, Alberto L Gallotti, Ilaria Pagano, Matteo Zanella, Stefania Mazzoleni, Flavia Pivetta, Monica Patanè, Giulia M Scotti, Ignazio S Piras, Bianca Pollo, Andrea Falini, Alessio Zippo, Antonella Castellano, Roberta Maestro, Pietro L Poliani, Rossella Galli.
      Medulloblastoma (MB), one of the most malignant brain tumors of childhood, comprises distinct molecular subgroups, with p53 mutant sonic hedgehog (SHH)-activated MB patients having a very severe outcome that is associated with unfavorable histological large cell/anaplastic (LC/A) features. To identify the molecular underpinnings of this phenotype, we analyzed a large cohort of MBs developing in p53-deficient Ptch+/- SHH mice that, unexpectedly, showed LC/A traits that correlated with mechanistic Target Of Rapamycin Complex 1 (mTORC1) hyperactivation. Mechanistically, mTORC1 hyperactivation was mediated by a decrease in the p53-dependent expression of mTORC1 negative regulator Tsc2. Ectopic mTORC1 activation in mouse MB cancer stem cells (CSCs) promoted the in vivo acquisition of LC/A features and increased malignancy; accordingly, mTORC1 inhibition in p53-mutant Ptch+/- SHH MBs and CSC-derived MBs resulted in reduced tumor burden and aggressiveness. Most remarkably, mTORC1 hyperactivation was detected only in p53-mutant SHH MB patients' samples and treatment with rapamycin of a human preclinical model phenocopying this subgroup decreased tumor growth and malignancy. Thus, mTORC1 may act as a specific druggable target for this subset of SHH MB, resulting in the implementation of a stringent risk stratification and in the potentially rapid translation of this precision medicine approach into the clinical setting.
    Keywords:  Brain cancer; Mouse models; Neuroscience; Oncology
    DOI:  https://doi.org/10.1172/jci.insight.153462
  7. Biomolecules. 2021 Oct 09. pii: 1489. [Epub ahead of print]11(10):
    Pib2 as an Emerging Master Regulator of Yeast TORC1.
    Riko Hatakeyama.
      Cell growth is dynamically regulated in response to external cues such as nutrient availability, growth factor signals, and stresses. Central to this adaptation process is the Target of Rapamycin Complex 1 (TORC1), an evolutionarily conserved kinase complex that fine-tunes an enormous number of cellular events. How upstream signals are sensed and transmitted to TORC1 has been intensively studied in major model organisms including the budding yeast Saccharomyces cerevisiae. This field recently saw a breakthrough: the identification of yeast phosphatidylInositol(3)-phosphate binding protein 2 (Pib2) protein as a critical regulator of TORC1. Although the study of Pib2 is still in its early days, multiple groups have provided important mechanistic insights on how Pib2 relays nutrient signals to TORC1. There remain, on the other hand, significant gaps in our knowledge and mysteries that warrant further investigations. This is the first dedicated review on Pib2 that summarizes major findings and outstanding questions around this emerging key player in cell growth regulation.
    Keywords:  Pib2; TOR; TORC1; mTOR; mTORC1; yeast
    DOI:  https://doi.org/10.3390/biom11101489
  8. Cells. 2021 Oct 09. pii: 2711. [Epub ahead of print]10(10):
    The SZT2 Interactome Unravels New Functions of the KICSTOR Complex.
    Cecilia Cattelani, Dominik Lesiak, Gudrun Liebscher, Isabel I Singer, Taras Stasyk, Moritz H Wallnöfer, Alexander M Heberle, Corrado Corti, Michael W Hess, Kristian Pfaller, Marcel Kwiatkowski, Peter P Pramstaller, Andrew A Hicks, Kathrin Thedieck, Thomas Müller, Lukas A Huber, Mariana Eca Guimaraes de Araujo.
      Seizure threshold 2 (SZT2) is a component of the KICSTOR complex which, under catabolic conditions, functions as a negative regulator in the amino acid-sensing branch of mTORC1. Mutations in this gene cause a severe neurodevelopmental and epileptic encephalopathy whose main symptoms include epilepsy, intellectual disability, and macrocephaly. As SZT2 remains one of the least characterized regulators of mTORC1, in this work we performed a systematic interactome analysis under catabolic and anabolic conditions. Besides numerous mTORC1 and AMPK signaling components, we identified clusters of proteins related to autophagy, ciliogenesis regulation, neurogenesis, and neurodegenerative processes. Moreover, analysis of SZT2 ablated cells revealed increased mTORC1 signaling activation that could be reversed by Rapamycin or Torin treatments. Strikingly, SZT2 KO cells also exhibited higher levels of autophagic components, independent of the physiological conditions tested. These results are consistent with our interactome data, in which we detected an enriched pool of selective autophagy receptors/regulators. Moreover, preliminary analyses indicated that SZT2 alters ciliogenesis. Overall, the data presented form the basis to comprehensively investigate the physiological functions of SZT2 that could explain major molecular events in the pathophysiology of developmental and epileptic encephalopathy in patients with SZT2 mutations.
    Keywords:  KICSTOR; SZT2; autophagy; ciliogenesis; epilepsy; mTORC1; neurodegeneration; neurogenesis
    DOI:  https://doi.org/10.3390/cells10102711
  9. PLoS Genet. 2021 Oct 21. 17(10): e1009832
    AKAP13 couples GPCR signaling to mTORC1 inhibition.
    Shihai Zhang, Huanyu Wang, Chase H Melick, Mi-Hyeon Jeong, Adna Curukovic, Shweta Tiwary, Tshering D Lama-Sherpa, Delong Meng, Kelly A Servage, Nicholas G James, Jenna L Jewell.
      The mammalian target of rapamycin complex 1 (mTORC1) senses multiple stimuli to regulate anabolic and catabolic processes. mTORC1 is typically hyperactivated in multiple human diseases such as cancer and type 2 diabetes. Extensive research has focused on signaling pathways that can activate mTORC1 such as growth factors and amino acids. However, less is known about signaling cues that can directly inhibit mTORC1 activity. Here, we identify A-kinase anchoring protein 13 (AKAP13) as an mTORC1 binding protein, and a crucial regulator of mTORC1 inhibition by G-protein coupled receptor (GPCR) signaling. GPCRs paired to Gαs proteins increase cyclic adenosine 3'5' monophosphate (cAMP) to activate protein kinase A (PKA). Mechanistically, AKAP13 acts as a scaffold for PKA and mTORC1, where PKA inhibits mTORC1 through the phosphorylation of Raptor on Ser 791. Importantly, AKAP13 mediates mTORC1-induced cell proliferation, cell size, and colony formation. AKAP13 expression correlates with mTORC1 activation and overall lung adenocarcinoma patient survival, as well as lung cancer tumor growth in vivo. Our study identifies AKAP13 as an important player in mTORC1 inhibition by GPCRs, and targeting this pathway may be beneficial for human diseases with hyperactivated mTORC1.
    DOI:  https://doi.org/10.1371/journal.pgen.1009832
  10. Cells. 2021 Oct 13. pii: 2730. [Epub ahead of print]10(10):
    Activation of mTORC1 by Free Fatty Acids Suppresses LAMP2 and Autophagy Function via ER Stress in Alcohol-Related Liver Disease.
    Wei Guo, Wei Zhong, Liuyi Hao, Xinguo Sun, Zhanxiang Zhou.
      Alcohol-related liver disease (ALD) is characterized by accumulation of hepatic free fatty acids (FFAs) and liver injury. The present study aimed to investigate if mechanistic target of rapamycin complex 1 (mTORC1) plays a role in FFA-induced organelle dysfunction, thereby contributing to the development of ALD. Cell studies were conducted to define the causal role and underlying mechanism of FFA-activated mTORC1 signaling in hepatocellular cell injury. C57BL/6J wild-type mice were subjected to chronic alcohol feeding with or without rapamycin to inhibit mTORC1 activation. We revealed that palmitic acid (PA)-induced ER stress and suppression of LAMP2 and autophagy flux were mTORC1-dependent as rapamycin reversed such deleterious effects. C/EBP homologous protein (CHOP) was downstream of ATF4 which partially modulated LAMP2. Supplementation with rapamycin to alcohol-fed mice attenuated mTORC1 activation and ER stress, restored LAMP2 protein, and improved autophagy, leading to amelioration of alcohol-induced liver injury. Induction of mTORC1 signaling and CHOP were also detected in the liver of patients with severe alcoholic hepatitis. This study demonstrates that hepatic FFAs play a crucial role in the pathogenesis of ALD by activating mTORC1 signaling, thereby inducing ER stress and suppressing LAMP2-autophagy flux pathway, which represents an important mechanism of FFA-induced hepatocellular injury.
    Keywords:  ER stress; LAMP2; alcohol-related liver disease; free fatty acid; inflammation; mTORC1
    DOI:  https://doi.org/10.3390/cells10102730
  11. J Appl Physiol (1985). 2021 Oct 21.
    REDD1 deletion attenuates cancer cachexia in mice.
    Brian A Hain, Haifang Xu, Ashley M VanCleave, Bradley S Gordon, Scot R Kimball, David L Waning.
      Cancer cachexia is a wasting disorder associated with advanced cancer that contributes to mortality. Cachexia is characterized by involuntary loss of body weight and muscle weakness that affects physical function. Regulated in DNA damage and development 1 (REDD1) is a stress-response protein that is transcriptionally upregulated in muscle during wasting conditions and inhibits mechanistic target of rapamycin complex 1 (mTORC1). C2C12 myotubes treated with Lewis lung carcinoma (LLC)-conditioned media increased REDD1 mRNA expression and decreased myotube diameter. To investigate the role of REDD1 in cancer cachexia, we inoculated 12-week old male wild-type or global REDD1 knockout (REDD1 KO) mice with LLC cells and euthanized 28-days later. Wild-type mice had increased skeletal muscle REDD1 expression, and REDD1 deletion prevented loss of body weight and lean tissue mass, but not fat mass. We found that REDD1 deletion attenuated loss of individual muscle weights and loss of myofiber cross sectional area. We measured markers of the Akt/mTORC1 pathway and found that, unlike wild-type mice, phosphorylation of both Akt and 4E-BP1 was maintained in the muscle of REDD1 KO mice after LLC inoculation, suggesting that loss of REDD1 is beneficial in maintaining mTORC1 activity in mice with cancer cachexia. We measured Foxo3a phosphorylation as a marker of the ubiquitin proteasome pathway and autophagy and found that REDD1 deletion prevented dephosphorylation of Foxo3a in muscles from cachectic mice. Our data provides evidence that REDD1 plays an important role in cancer cachexia through the regulation of both protein synthesis and protein degradation pathways.
    Keywords:  REDD1; cachexia; muscle
    DOI:  https://doi.org/10.1152/japplphysiol.00536.2021
  12. J Biol Eng. 2021 Oct 21. 15(1): 24
    AZD2014, a dual mTOR inhibitor, attenuates cardiac hypertrophy in vitro and in vivo.
    Byung-Hyun Cha, Minjin Jung, Angela S Kim, Victoria C Lepak, Brett A Colson, David A Bull, Youngwook Won.
      Cardiac hypertrophy is one of the most common genetic heart disorders and considered a risk factor for cardiac morbidity and mortality. The mammalian target of rapamycin (mTOR) pathway plays a key regulatory function in cardiovascular physiology and pathology in hypertrophy. AZD2014 is a small-molecule ATP competitive mTOR inhibitor working on both mTORC1 and mTORC2 complexes. Little is known about the therapeutic effects of AZD2014 in cardiac hypertrophy and its underlying mechanism. Here, AZD2014 is examined in in vitro model of phenylephrine (PE)-induced human cardiomyocyte hypertrophy and a myosin-binding protein-C (Mybpc3)-targeted knockout (KO) mouse model of cardiac hypertrophy. Our results demonstrate that cardiomyocytes treated with AZD2014 retain the normal phenotype and AZD2014 attenuates cardiac hypertrophy in the Mybpc3-KO mouse model through inhibition of dual mTORC1 and mTORC2, which in turn results in the down-regulation of the Akt/mTOR signaling pathway.
    Keywords:  AZD2014; Cardiac hypertrophy; Cardiomyocyte; mTOR inhibitor
    DOI:  https://doi.org/10.1186/s13036-021-00276-3
  13. J Cachexia Sarcopenia Muscle. 2021 Oct 19.
    Loss of REDD1 prevents chemotherapy-induced muscle atrophy and weakness in mice.
    Brian A Hain, Haifang Xu, David L Waning.
      BACKGROUND: Chemotherapy is an essential treatment to combat solid tumours and mitigate metastasis. Chemotherapy causes side effects including muscle wasting and weakness. Regulated in Development and DNA Damage Response 1 (REDD1) is a stress-response protein that represses the mechanistic target of rapamycin (mTOR) in complex 1 (mTORC1), and its expression is increased in models of muscle wasting. The aim of this study was to determine if deletion of REDD1 is sufficient to attenuate chemotherapy-induced muscle wasting and weakness in mice.METHODS: C2C12 myotubes were treated with carboplatin, and changes in myotube diameter were measured. Protein synthesis was measured by puromycin incorporation, and REDD1 mRNA and protein expression were analysed in myotubes treated with carboplatin. Markers of mTORC1 signalling were measured by western blot. REDD1 global knockout mice and wild-type mice were treated with a single dose of carboplatin and euthanized 7 days later. Body weight, hindlimb muscle weights, forelimb grip strength, and extensor digitorum longus whole muscle contractility were measured in all groups. Thirty minutes prior to euthanasia, mice were injected with puromycin to measure puromycin incorporation in skeletal muscle.
    RESULTS: C2C12 myotube diameter was decreased at 24 (P = 0.0002) and 48 h (P < 0.0001) after carboplatin treatment. Puromycin incorporation was decreased in myotubes treated with carboplatin for 24 (P = 0.0068) and 48 h (P = 0.0008). REDD1 mRNA and protein expression were increased with carboplatin treatment (P = 0.0267 and P = 0.0015, respectively), and this was accompanied by decreased phosphorylation of Akt T308 (P < 0.0001) and S473 (P = 0.0006), p70S6K T389 (P = 0.0002), and 4E-binding protein 1 S65 (P = 0.0341), all markers of mTORC1 activity. REDD1 mRNA expression was increased in muscles from mice treated with carboplatin (P = 0.0295). Loss of REDD1 reduced carboplatin-induced body weight loss (P = 0.0013) and prevented muscle atrophy in mice. REDD1 deletion prevented carboplatin-induced decrease of protein synthesis (P = 0.7626) and prevented muscle weakness.
    CONCLUSIONS: Carboplatin caused loss of body weight, muscle atrophy, muscle weakness, and inhibition of protein synthesis. Loss of REDD1 attenuates muscle atrophy and weakness in mice treated with carboplatin. Our study illustrates the importance of REDD1 in the regulation of muscle mass with chemotherapy treatment and may be an attractive therapeutic target to combat cachexia.
    Keywords:  Cachexia; Chemotherapy; Muscle atrophy; Muscle weakness; Protein synthesis; REDD1
    DOI:  https://doi.org/10.1002/jcsm.12795
  14. Nat Commun. 2021 Oct 19. 12(1): 6084
    mTOR-related synaptic pathology causes autism spectrum disorder-associated functional hyperconnectivity.
    Marco Pagani, Noemi Barsotti, Alice Bertero, Stavros Trakoshis, Laura Ulysse, Andrea Locarno, Ieva Miseviciute, Alessia De Felice, Carola Canella, Kaustubh Supekar, Alberto Galbusera, Vinod Menon, Raffaella Tonini, Gustavo Deco, Michael V Lombardo, Massimo Pasqualetti, Alessandro Gozzi.
      Postmortem studies have revealed increased density of excitatory synapses in the brains of individuals with autism spectrum disorder (ASD), with a putative link to aberrant mTOR-dependent synaptic pruning. ASD is also characterized by atypical macroscale functional connectivity as measured with resting-state fMRI (rsfMRI). These observations raise the question of whether excess of synapses causes aberrant functional connectivity in ASD. Using rsfMRI, electrophysiology and in silico modelling in Tsc2 haploinsufficient mice, we show that mTOR-dependent increased spine density is associated with ASD -like stereotypies and cortico-striatal hyperconnectivity. These deficits are completely rescued by pharmacological inhibition of mTOR. Notably, we further demonstrate that children with idiopathic ASD exhibit analogous cortical-striatal hyperconnectivity, and document that this connectivity fingerprint is enriched for ASD-dysregulated genes interacting with mTOR or Tsc2. Finally, we show that the identified transcriptomic signature is predominantly expressed in a subset of children with autism, thereby defining a segregable autism subtype. Our findings causally link mTOR-related synaptic pathology to large-scale network aberrations, revealing a unifying multi-scale framework that mechanistically reconciles developmental synaptopathy and functional hyperconnectivity in autism.
    DOI:  https://doi.org/10.1038/s41467-021-26131-z
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