26 research outputs found
Vieillissement musculaire : impact de la protéolyse intracellulaire calcium-dépendante
La sarcopĂ©nie ou perte involontaire progressive de la masse musculaire chez le sujet ĂągĂ© sâaccompagne de lâaltĂ©ration de nombreux phĂ©nomĂšnes physiologiques comparables Ă ceux observĂ©s chez les myopathes. Le processus de rĂ©gĂ©nĂ©ration musculaire est trĂšs ralenti, les activitĂ©s protĂ©olytiques intracellulaires sont modifiĂ©es et de nombreuses fonctions cellulaires sont perturbĂ©es en raison dâun stress oxydatif incontrĂŽlĂ©. Lâintervention des calpaĂŻnes, protĂ©ases neutres calcium-dĂ©pendantes, dans les processus associĂ©s au dĂ©veloppement, Ă la rĂ©gĂ©nĂ©ration et Ă lâintĂ©gritĂ© du tissu musculaire est incontestable. Les calpaĂŻnes apparaissent, en effet, comme des acteurs clefs des voies de transductions liĂ©es Ă la myogenĂšse, la prolifĂ©ration et la survie cellulaire. Toutefois aucune Ă©tude permettant dâĂ©tablir la relation vieillissement du tissu musculaire- activitĂ© calpaĂŻne nâa Ă©tĂ© entreprise Ă ce jour. Le projet a donc pour but principal dâinventorier les signaux pro-sarcopĂ©niques interagissant avec les calpaĂŻnes et dâĂ©tablir leurs relations avec la fonctionnalitĂ© des cellules satellites, le stress oxydant et lâapoptose. Nous avons mis en Ă©vidence une augmentation de lâexpression/activitĂ© des calpaĂŻnes durant le vieillissement musculaire chez le rat et identifiĂ© des partenaires des calpaĂŻnes impliquĂ©s dans des fonctions physiologiques altĂ©rĂ©es durant la sarcopĂ©nie: homĂ©ostasie calcique, activitĂ© contractile, production dâATP, rĂ©gĂ©nĂ©ration musculaire. Nous avons Ă©galement montrĂ© que lâinduction dâun stress oxydant entraĂźne lâactivation des calpaĂŻnes au cours de la prolifĂ©ration des cellules satellites de façon corrĂ©lĂ©e Ă une augmentation de lâapoptose. Dâune maniĂšre intĂ©ressante, un traitement prĂ©ventif par un antioxydant naturel dâĂ©corce de pin (OligopinÂź) est capable de prĂ©venir Ă la fois lâapoptose et lâactivation des calpaĂŻnes. Lâensemble de ces rĂ©sultats suggĂšre que le stress oxydant associĂ© au vieillissement induirait des mĂ©canismes calpaĂŻno-dĂ©pendants responsables de lâaltĂ©ration de processus essentiels Ă la fonction musculaire.Aging is associated with a progressive and involuntary loss of muscle mass also known as sarcopenia. This condition represents a major public health concern. Although sarcopenia is well documented, the molecular mechanisms of this condition still remain unclear. The calcium-dependent proteolytic system is composed of calcium dependent cystein-proteases named calpains. Calpains are involved in a large number of physiological processes such as muscle growth and differentiation, and pathological conditions such as muscular dystrophies. The aim of this study was to determine the involvement of the proteolytic system in the phenotype associated with sarcopenia by identify the key proteins (substrates or regulators) interacting with calpains during muscle aging and identify pro-sarcopenic signals after oxidative stress induction in satellite cells. Muscle aging was correlated with the up-regulation of calpain activity. Ryanodine receptor 1, ATP synthase subunit alpha and alpha actinin 3 appear as key partners of calpains during muscle aging. Such interactions suggest an implication of calpains in many processes altered during aging including cytoskeletal disorganisation, regulation of calcium homeostasis and mitochondrial dysfunction. Furthermore, oxidative stress induction led to an increase in the activity of calpains correlated to an increase in apoptosis of proliferating satellite cells. In a very interesting way, a preventive treatment with a commercial antioxidant (OligopinÂź) prevented these effects. All these data suggest that oxidative stress coupled observed during muscle aging could lead to calpaĂŻno-dependent mechanisms responsible for apoptosis and muscle dysorganisation
Vieillissement musculaire : impact de la protéolyse intracellulaire calcium-dépendante
La sarcopĂ©nie ou perte involontaire progressive de la masse musculaire chez le sujet ĂągĂ© sâaccompagne de lâaltĂ©ration de nombreux phĂ©nomĂšnes physiologiques comparables Ă ceux observĂ©s chez les myopathes. Le processus de rĂ©gĂ©nĂ©ration musculaire est trĂšs ralenti, les activitĂ©s protĂ©olytiques intracellulaires sont modifiĂ©es et de nombreuses fonctions cellulaires sont perturbĂ©es en raison dâun stress oxydatif incontrĂŽlĂ©. Lâintervention des calpaĂŻnes, protĂ©ases neutres calcium-dĂ©pendantes, dans les processus associĂ©s au dĂ©veloppement, Ă la rĂ©gĂ©nĂ©ration et Ă lâintĂ©gritĂ© du tissu musculaire est incontestable. Les calpaĂŻnes apparaissent, en effet, comme des acteurs clefs des voies de transductions liĂ©es Ă la myogenĂšse, la prolifĂ©ration et la survie cellulaire. Toutefois aucune Ă©tude permettant dâĂ©tablir la relation vieillissement du tissu musculaire- activitĂ© calpaĂŻne nâa Ă©tĂ© entreprise Ă ce jour. Le projet a donc pour but principal dâinventorier les signaux pro-sarcopĂ©niques interagissant avec les calpaĂŻnes et dâĂ©tablir leurs relations avec la fonctionnalitĂ© des cellules satellites, le stress oxydant et lâapoptose. Nous avons mis en Ă©vidence une augmentation de lâexpression/activitĂ© des calpaĂŻnes durant le vieillissement musculaire chez le rat et identifiĂ© des partenaires des calpaĂŻnes impliquĂ©s dans des fonctions physiologiques altĂ©rĂ©es durant la sarcopĂ©nie: homĂ©ostasie calcique, activitĂ© contractile, production dâATP, rĂ©gĂ©nĂ©ration musculaire. Nous avons Ă©galement montrĂ© que lâinduction dâun stress oxydant entraĂźne lâactivation des calpaĂŻnes au cours de la prolifĂ©ration des cellules satellites de façon corrĂ©lĂ©e Ă une augmentation de lâapoptose. Dâune maniĂšre intĂ©ressante, un traitement prĂ©ventif par un antioxydant naturel dâĂ©corce de pin (OligopinÂź) est capable de prĂ©venir Ă la fois lâapoptose et lâactivation des calpaĂŻnes. Lâensemble de ces rĂ©sultats suggĂšre que le stress oxydant associĂ© au vieillissement induirait des mĂ©canismes calpaĂŻno-dĂ©pendants responsables de lâaltĂ©ration de processus essentiels Ă la fonction musculaire.Aging is associated with a progressive and involuntary loss of muscle mass also known as sarcopenia. This condition represents a major public health concern. Although sarcopenia is well documented, the molecular mechanisms of this condition still remain unclear. The calcium-dependent proteolytic system is composed of calcium dependent cystein-proteases named calpains. Calpains are involved in a large number of physiological processes such as muscle growth and differentiation, and pathological conditions such as muscular dystrophies. The aim of this study was to determine the involvement of the proteolytic system in the phenotype associated with sarcopenia by identify the key proteins (substrates or regulators) interacting with calpains during muscle aging and identify pro-sarcopenic signals after oxidative stress induction in satellite cells. Muscle aging was correlated with the up-regulation of calpain activity. Ryanodine receptor 1, ATP synthase subunit alpha and alpha actinin 3 appear as key partners of calpains during muscle aging. Such interactions suggest an implication of calpains in many processes altered during aging including cytoskeletal disorganisation, regulation of calcium homeostasis and mitochondrial dysfunction. Furthermore, oxidative stress induction led to an increase in the activity of calpains correlated to an increase in apoptosis of proliferating satellite cells. In a very interesting way, a preventive treatment with a commercial antioxidant (OligopinÂź) prevented these effects. All these data suggest that oxidative stress coupled observed during muscle aging could lead to calpaĂŻno-dependent mechanisms responsible for apoptosis and muscle dysorganisation
2.03 - Penicillins
This chapter outlines selected recent developments, together with some reminders of traditional methods, in the chemistry of penams A (4-thia-1-azabicyclo[3.2.0]heptan-7-one) and penems B (4-thia-1-azabicyclo[3.2.0]hept-2-en-7-one). Under the generic term of âpenicillinsâ, they are part of the most important family of antibacterial agents in current therapeutic use. The common structural feature of these drugs is an azetidin-2-one ring (ÎČ-lactam) fused to a five-membered ring
Calcium-dependent proteolytic system and muscle dysfunctions: A possible role of calpains in sarcopenia
International audienceThe calcium-dependent proteolytic system is composed of cysteine proteases named calpains. They are ubiquitous or tissue-specific enzymes. The two best characterised isoforms are the ubiquitously expressed mu- and m-calpains. Besides its regulation by calcium, calpain activity is tightly controlled by calpastatin, the specific endogenous inhibitor, binding to phospholipids, autoproteolysis and phosphorylation. Calpains are responsible for limited proteolytic events. Among the multitude of substrates identified so far are cytoskeletal and membrane proteins, enzymes and transcription factors. Calpain activity is involved in a large number of physiological and pathological processes. In this review, we will particularly focus on the implication of the calcium-dependent proteolytic system in relation to muscle physiology. Because of their ability to remodel cytoskeletal anchorage complexes, calpains play a major role in the regulation of cell adhesion, migration and fusion, three key steps of myogenesis. Calcium-dependent proteolysis is also involved in the control of cell cycle. In muscle tissue, in particular, calpains intervene in the regeneration process. Another important class of calpain substrates belongs to apoptosis regulating factors. The proteases may thus play a role in muscle cell death, and as a consequence in muscle atrophy. The relationships between calcium-dependent proteolysis and muscle dysfunctions are being further developed in this review with a particular emphasis on sarcopenia
Fluoride-induced coupling of perfluoroketene dithioacetals with silyl alkynes: A way towards new polyfunctionalized trifluoromethyl building blocks
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Good People Behave, Bad People Design. Misbehaving as a Methodological Framework for Design and Design Education
International audienceWhat happens when unwanted or unexpected attitudes infiltrate design processes, artifacts and uses? This paper focuses on misbehaving as part of the paradigm of design research that explores new ways to think our objects, spaces and interactions. We built upon a mosaic of case-studies and conceptual inputs to identify how âmisbehaving attitudesâ may operate within contexts informed by habitus, norms, regulations, standards, protocols, procedures, and/or laws. The hypothesis of this in-progress research is that these attitudes should be considered as potential methodological approaches that can enrich and extend the most âclassicalâ practices of design. To put it forthright: can âmisbehavingâ approaches in design enhance the practices of design? To conclude, this paper will discuss how âmisbehavingâ in design education could foster the âcritical thinkingâ advocated in numerous curriculums (Combs, Cennamo & Newbill, 2009; Finn, Baum & Newbill, 2011; MinistĂšre de lâEnseignement SupĂ©rieur et de la Recherche, 2012; etc.)
Proteomic study of calpain interacting proteins during skeletal muscle aging
International audienceAging is associated with a progressive and involuntary loss of muscle mass also known as sarcopenia. This condition represents a major public health concern. Although sarcopenia is well documented, the molecular mechanisms of this condition still remain unclear. The calcium-dependent proteolytic system is composed of calcium-dependent cysteine proteases named calpains. Calpains are involved in a large number of physiological processes such as muscle growth and differentiation, and pathological conditions such as muscular dystrophies. The aim of this study was to determine the involvement of this proteolytic system in the phenotype associated with sarcopenia by identifying key proteins (substrates or regulators) interacting with calpains during muscle aging. Immunoprecipitations coupled with proteomic analyses and protein identification by mass spectrometry have been undertaken. Reverse co-immunoprecipitation, cellular colocalisation by confocal microscopy and calpain-dependent in vitro proteolysis of several of the identified proteins have been also carried out. We identified ATP synthase subunit alpha and alpha actinin 3 as key partners of calpains during muscle aging. Such interactions would suggest that calpains are implicated in many processes altered during aging including cytoskeletal disorganisation and mitochondrial dysfunction
Up-regulation of calcium-dependent proteolysis in human myoblasts under acute oxidative stress
International audienceThe reduced regenerative potential of muscle fibres, most likely due to a decreased number and/or function of satellite cells, could play a significant role in the progression of muscle ageing. Accumulation of reactive oxygen species has been clearly correlated to sarcopenia and could contribute to the impairment of satellite cell function. In this work we have investigated the effect of oxidative stress generated by hydrogen peroxide in cultured human skeletal muscle satellite cells. We specifically focused on the activity and regulation of calpains. These calcium-dependent proteases are known to regulate many transduction pathways including apoptosis and play a critical role in satellite cell function. In our experimental conditions, which induce an increase in calcium concentration, protein oxidation and apoptotic cell death, a significant up-regulation of calpain expression and activity were observed and ATP synthase, a major component of the respiratory chain, was identified as a calpain target. Interestingly we were able to protect the cells from these H2O2-induced effects and prevent calpain up-regulation with a natural antioxidant extracted from pine bark (OligopinÂź). These data strongly suggest that oxidative stress could impair satellite cell functionality via calpain-dependent pathways and that an antioxidant such as OligopinÂź could prevent apoptosis and calpain activation
Biased signaling regulates the pleiotropic effects of the urotensin II receptor to modulate its cellular behaviors
International audienceBiased agonism by G-protein-coupled receptor ligands has opened up strategies for targeted physiological or therapeutic actions. We hypothesized that urotensin II (UII)-derived peptides displayed unexpected physiological effects because of such biased signaling on the UII human urotensin (hUT) receptor. We determined the coupling to G proteins and beta-arrestins of the UII-activated hUT receptor expressed in HEK293 using bioluminescence resonance energy transfer (BRET) biosensors, as well as the production of IP1-3 and cAMP using homogenous time-resolved Forster resonance energy transfer (FRET) (HTRF)-based assays. The activated receptor coupled to Gi1, GoA, Gq, and G13, excluding Gs, and recruited beta-arrestins 1 and 2. Integration of these pathways led to a 2-phase kinetic phosphorylation of ERK1/2 kinases. The tested peptides induced three different profiles: UII, urotensin-related peptide (URP), and UII4-11 displayed the full profile; [Orn(8)]UII and [Orn(5)]URP activated G proteins, although with pEC50s 5-10x higher, and did not or barely recruited beta-arrestin; urantide also failed to recruit beta-arrestin but displayed a reversed rank order for Gi and Gq vs. Go pEC50s (-8.79+/-0.20, -8.43+/-0.21, and -7.86+/-0.36, respectively, for urantide, -7.87+/-0.10, -7.23+/-0.27, and -8.55+/-0.19, respectively, for [Orn(5)]URP) and was a partial agonist of all G-protein pathways. Interestingly, the peptides differently modulated cell survival but similarly induced cell migration and adhesion. Thus, we demonstrate biased signaling between beta-arrestin and G proteins, and between G-protein subtypes, which dictates the receptor's cellular responses