TNF-α- and tumor-induced skeletal muscle atrophy involves sphingolipid metabolism

Additional filesInternational audienceUNLABELLED: ABSTRACT: BACKGROUND: Muscle atrophy associated with various pathophysiological conditions represents a major health problem, because of its contribution to the deterioration of patient status and its effect on mortality. Although the involvement of pro-inflammatory cytokines in this process is well recognized, the role of sphingolipid metabolism alterations induced by the cytokines has received little attention. RESULTS: We addressed this question both in vitro using differentiated myotubes treated with TNF-α, and in vivo in a murine model of tumor-induced cachexia. Myotube atrophy induced by TNF-α was accompanied by a substantial increase in cell ceramide levels, and could be mimicked by the addition of exogenous ceramides. It could be prevented by the addition of ceramide-synthesis inhibitors that targeted either the de novo pathway (myriocin), or the sphingomyelinases (GW4869 and 3-O-methylsphingomyelin). In the presence of TNF-α, ceramide-synthesis inhibitors significantly increased protein synthesis and decreased proteolysis. In parallel, they lowered the expression of both the Atrogin-1 and LC3b genes, involved in muscle protein degradation by proteasome and in autophagic proteolysis, respectively, and increased the proportion of inactive, phosphorylated Foxo3 transcription factor. Furthermore, these inhibitors increased the expression and/or phosphorylation levels of key factors regulating protein metabolism, including phospholipase D, an activator of mammalian target of rapamycin (mTOR), and the mTOR substrates S6K1 and Akt. In vivo, C26 carcinoma implantation induced a substantial increase in muscle ceramide, together with drastic muscle atrophy. Treatment of the animals with myriocin reduced the expression of the atrogenes Foxo3 and Atrogin-1, and partially protected muscle tissue from atrophy. CONCLUSIONS: Ceramide accumulation induced by TNF-α or tumor development participates in the mechanism of muscle-cell atrophy, and sphingolipid metabolism is a logical target for pharmacological or nutritional interventions aiming at preserving muscle mass in pathological situations

Neonatal Screening in Europe Revisited: An ISNS Perspective on the Current State and Developments Since 2010

Neonatal screening (NBS) was initiated in Europe during the 1960s with the screening for phenylketonuria. The panel of screened disorders (“conditions”) then gradually expanded, with a boost in the late 1990s with the introduction of tandem mass spectrometry (MS/MS), making it possible to screen for 40–50 conditions using a single blood spot. The most recent additions to screening programmes (screening for cystic fibrosis, severe combined immunodeficiency and spinal muscular atrophy) were assisted by or realised through the introduction of molecular technologies. For this survey, we collected data from 51 European countries. We report the developments between 2010 and 2020 and highlight the achievements reached with the progress made in this period. We also identify areas where further progress can be made, mainly by exchanging knowledge and learning from experiences in neighbouring countries. Between 2010 and 2020, most NBS programmes in geographical Europe matured considerably, both in terms of methodology (modernised) and with regard to the panel of conditions screened (expanded). These developments indicate that more collaboration in Europe through European organisations is gaining momentum. We can only accomplish the timely detection of newborn infants potentially suffering from one of the many rare diseases and take appropriate action by working together

Early Neurodegeneration Progresses Independently of Microglial Activation by Heparan Sulfate in the Brain of Mucopolysaccharidosis IIIB Mice

BACKGROUND: In mucopolysaccharidosis type IIIB, a lysosomal storage disease causing early onset mental retardation in children, the production of abnormal oligosaccharidic fragments of heparan sulfate is associated with severe neuropathology and chronic brain inflammation. We addressed causative links between the biochemical, pathological and inflammatory disorders in a mouse model of this disease. METHODOLOGY/PRINCIPAL FINDINGS: In cell culture, heparan sulfate oligosaccharides activated microglial cells by signaling through the Toll-like receptor 4 and the adaptor protein MyD88. CD11b positive microglial cells and three-fold increased expression of mRNAs coding for the chemokine MIP1alpha were observed at 10 days in the brain cortex of MPSIIIB mice, but not in MPSIIIB mice deleted for the expression of Toll-like receptor 4 or the adaptor protein MyD88, indicating early priming of microglial cells by heparan sulfate oligosaccharides in the MPSIIIB mouse brain. Whereas the onset of brain inflammation was delayed for several months in doubly mutant versus MPSIIIB mice, the onset of disease markers expression was unchanged, indicating similar progression of the neurodegenerative process in the absence of microglial cell priming by heparan sulfate oligosaccharides. In contrast to younger mice, inflammation in aged MPSIIIB mice was not affected by TLR4/MyD88 deficiency. CONCLUSIONS/SIGNIFICANCE: These results indicate priming of microglia by HS oligosaccharides through the TLR4/MyD88 pathway. Although intrinsic to the disease, this phenomenon is not a major determinant of the neurodegenerative process. Inflammation may still contribute to neurodegeneration in late stages of the disease, albeit independent of TLR4/MyD88. The results support the view that neurodegeneration is primarily cell autonomous in this pediatric disease

Neonatal Screening in Europe Revisited: An ISNS Perspective on the Current State and Developments Since 2010

Neonatal screening (NBS) was initiated in Europe during the 1960s with the screening for phenylketonuria. The panel of screened disorders ("conditions") then gradually expanded, with a boost in the late 1990s with the introduction of tandem mass spectrometry (MS/MS), making it possible to screen for 40-50 conditions using a single blood spot. The most recent additions to screening programmes (screening for cystic fibrosis, severe combined immunodeficiency and spinal muscular atrophy) were assisted by or realised through the introduction of molecular technologies. For this survey, we collected data from 51 European countries. We report the developments between 2010 and 2020 and highlight the achievements reached with the progress made in this period. We also identify areas where further progress can be made, mainly by exchanging knowledge and learning from experiences in neighbouring countries. Between 2010 and 2020, most NBS programmes in geographical Europe matured considerably, both in terms of methodology (modernised) and with regard to the panel of conditions screened (expanded). These developments indicate that more collaboration in Europe through European organisations is gaining momentum. We can only accomplish the timely detection of newborn infants potentially suffering from one of the many rare diseases and take appropriate action by working together

APPLICATION DE LA CYTOMETRIE EN FLUX A L'ETUDE DES DEFICITS FONCTIONNELS DES POLYNUCLEAIRES NEUTROPHILES CHEZ L'HOMME (DES BIOL.MED.)

LYON1-BU Santé (693882101) / SudocSudocFranceF

Apport de l'étude du gène ABCD1 dans le diagnostic de l'adrénoleucodystrophie liée à l'X

LYON1-BU Santé (693882101) / SudocSudocFranceF

Approche thérapeutique d'une maladie génétique rare ( le déficit de synthèse en créatine par déficit en guanidinoacétate méthyltransferase)

LYON1-BU Santé (693882101) / SudocSudocFranceF

Screening des gènes PEX dans les déficits héréditaires de la biogenèse des peroxysomes

LYON1-BU Santé (693882101) / SudocSudocFranceF

Etude du gène PEX7 dans la chondrodysplasie rhinomélique ponctuée péroxysomale de type 1

La Chondrodysplasie Rhizomélique Ponctuée de type 1 (CDRP-1) est une pathologie peroxysomale appartenant au groupe des anomalies de la biogenèse des peroxysomes. C'est une maladie rare à transmission autosomique récessive. Elle recouvre un spectre d'expression clinique dont la forme classique est caractérisée par un raccourcissement des os longs proximaux, une calcification ponctuée des articulations, une atteinte du système nerveux et au niveau biochimique, par un déficit en plasmalogènes. Le décès survient souvent pendant la première année de vie. Cependant, certains phénotypes atypiques peuvent entraîner une survie jusqu'à l'âge adulte. Cette variabilité phénotypique est la conséquence d'une hétérogénéité allélique dans le gène PEX7. Le diagnostic repose à la fois sur des arguments cliniques, sur l'imagerie et sur l'exploration des fonctions peroxysomales. In utero, il est possible d'observer des signes d'appel échographiques, mais ils n'apparaissent pas avant le 2ème trimestre de grossesse. Les autres formes de chondrodysplasies sont souvent difficiles à différencier. Une confirmation par des méthodes biochimiques complexes sur cellules est donc indispensable. Le diagnostic prénatal est par conséquent difficile car il nécessite un délai de trois semaines, nécessaires à la culture cellulaire et l'interprétation des résultats est parfois difficile. De plus, un résultat négatif ne permet pas d'exclure formellement une CDRP d'origine peroxysomale. L'objectif de notre travail a consisté en la mise en place du dosage des plasmalogènes afin de confirmer l'origine peroxysomale de la chondrodysplasie. Puis, par la mise au point de l'étude du gène PEX7 nous avons établi le diagnostic moléculaire de la plus fréquente des CDRP peroxysomale : la CDRP-1. Ce travail nous a permis de confirmer le déficit en Pex7p chez 11 patients parmi les 19 étudiés et de décrire cmq nouvelles mutations : c.1 OOdupT (p.Cys34LeufsX22), c.646_687dup42nt (p.Thr216_Arg229dup14), c.683dupT (p.Leu228PhefsX10), c.745delA (p.Lys249AsnfsX19) et c.922G>T (p.Asp308Tyr). Pour 8 patients, aucune mutation n'a été trouvée donc une autre étiologie est à rechercher. Le diagnostic de certitude de la CDRP-1 chez les cas index par une étude moléculaire est ainsi disponible en France. Il s'agit d'un outil précit;ux qui permet de proposer aux familles un conseil génétique et un diagnostic prénatal rapideLYON1-BU Santé (693882101) / SudocSudocFranceF

Do we need congenital adrenal hyperplasia screening for premature infants?

International audienceCongenital adrenal hyperplasia neonatal screening has been introduced in France since 1995. A recent survey has questioned its relevance in premature infants because of a high number of false positives and a low positive predictive value of 17-hydroxyprogesterone dosage. A workgroup at the French screening association (Association francaise de depistage et de prevention des handicaps de l'enfant) collected all the epidemiological, clinical and biological data of premature children presenting with adrenal hyperplasia from the national cohort. Their results were compared with those of healthy premature children. All the data showed that the screening in children born before 32 weeks of gestational age is irrelevant, but that it is efficient after this term. A pilot study has been implemented in population to evaluate the opportunity to discontinue this screening in extreme preterm neonates