Wednesday May 17th à 14:00 – Salle Guillermond - Bât. L’Herbier
Normandie Rouen University / Inserm 1239 – Team Astrocyte and Vascular Niche.
Cancer and Cancer treatments on cognition: A major translational impact of the preclinical research
Invited by Virginie DESESTRET
Co-head Cancer and Neurosciences axis Northwest canceropole, Cancer and cognition platform; ICCTF member (editing of preclinical research guidelines).
The emergence of a new field in oncology addressing cognitive deficits in cancer patients is justified by the existence of deficits in memory, concentration and attention, as well as executive functions before, during and after treatments, symptoms often referring to the “chemofog” or “cancerfog”. Our work mainly involves research and clinical groups of Normandie developing programs in patients and animal models, to improve our understanding of the impact of cancer and its treatments on cognitive functions. Two main examples of these translational studies we participated on can be exposed:
The first Cog-Age clinical study (Pr F. Joly, Baclesse Caen) showed that cognitive decline can be detected 6 months after chemotherapy in breast cancer elderly patients. In a mirror study, chemotherapy administration in young and elderly mice resulted in a change in behavioral flexibility and alteration of neuron precursor proliferation in the hippocampal dentate gyrus. We were thus able to conclude that age-related cognitive decline is accentuated by chemotherapy, providing basis for questioning the place of adjuvant chemotherapy in this elderly patient population. The second clinical study COG-ANGIO (Pr Joly) demonstrated that antiangiogenics exert a direct negative impact on cognitive functions and fatigue in kidney cancer patients. In mice, the anti-angiogenic mTOR inhibitor everolimus did not alter cognitive functions but led to weight loss and modification of cell metabolism in brain regions involved in sleep/wake cycle or food intake, likely connected to fatigue. On the other hand, immunoneutralizing VEGF (Genentech-Roche, MTA) impaired spatial learning performance and neuronal activity of CA3 hippocampus neurons. These data suggest that a careful and systematic evaluation of targeted cancer therapies on cognitive functions in preclinical models may constitute a strategy of prevention by selection of treatments exhibiting minimum brain co-morbidities.
Together, this translational program is developed within the National Cancer and Cognition Platform (CNO/Ligue Nationale contre le cancer), with the aim to collaborate in a structured way with French oncology groups, research teams as well as pharmaceutical industry, by providing preclinical models and guidance on standard operating procedures for ancillary or future studies in identified population at risk.
Friday March 31st à 11:00 – Salle FONTANNES - Bât. Darwin D RdC
Institut des Nestlé Institute of Health Sciences SA, Lausanne.
Key signaling players in the control of hepatic gluconeogenesis --- AMPK or other AMPK-related/AMP-regulated enzymes ?
Invited by Rémi Mounier
Hepatic glucose production is a key physiologic process that ensures energy balance for glucose-dependent organs/cells such as brain. The inability of insulin to suppress hepatic glucose output is a major aetiological factor in the hyperglycaemia of type 2 diabetes. LKB1, originally identified as a tumor suppressor protein, is currently thought as a critical regulator of cellular metabolism and growth by controlling the activity of AMP-activated protein kinase (AMPK) and also 12 other kinases that are closely related to AMPK. Among those AMPK-related kinases, we have recently identified that Salt-Inducible Kinase (SIK) plays an important role as a gluconeogenic gatekeeper in the liver.
Metformin exerts its major effect via inhibition of hepatic glucose production. This is thought to be mediated through decreased hepatic energy charge (i.e. increasing AMP/ATP ratio) via inhibition of mitochondrial respiration. The long-standing belief that 5’-adenosine monophosphate (AMP)-activated protein kinase (AMPK) mediates the anti-hyperglycaemic action of metformin has recently been challenged in experiments using mice lacking hepatic AMPK. I will discuss our recent data demonstrating AMP-mediated allosteric inhibition of an enzyme involved in gluconeogenesis plays a key role in acute glucose-lowering effect of metformin.
Thursday January 12th at 14:00 – Amphithéâtre CNRS
Institut des Neurosciences de Montpellier, INSERM U1051. France.
Heterogeneous precursor populations underlie developmental plasticity of the dorsal root ganglia
Invited by Valérie Castellani
Although a variety of primary sensory neurons are implicated in the detection and transmission of different sensory modalities, how they arise during development remains poorly understood. The process of neuronal specification is the acquisition of definitive phenotypic characteristics for a given subclass of neurons during embryonic development. This acquisition can be divided into several interdependent and sequential phases, from the time point when progenitor cells exit the cell cycle toward the newly formed and perfectly differentiated neuron. Using mouse genetics, Alexandre demonstrated that transcriptions factors of Maf and Zeb families control the specification and differentiation of specific sensory neuron sub-types. His work contributed to uncover the complex developmental sequence ensuring the formation of the peripheral sensory system and to highlight the progenitor diversity that underlies the developmental plasticity of sensory neuron generation.
Jeudi 19 Janvier à 11:00 – Salle FONTANNES - Bât. Darwin D RdC
The Rockefeller University, Shaham lab, New York, USA.
It takes two to tango with elegance: Glia and pioneer neurons orchestrate C. elegans brain assembly
Invited by Jean-Louis Bessereau
Brain assembly is hypothesized to begin when pioneer axons extend over non-neuronal cells, forming tracts guiding follower axons. Yet, the identities of the pioneer-neurons and of their guidance-substrates and their interactions, are not well understood. Here, using time-lapse embryonic imaging, genetics, protein-interaction, and functional studies, we uncover the early events of C. elegans brain assembly. We demonstrate that C. elegans possesses radial-glia-like cells key for assembly initiation. Glia guide pioneer and follower axons using distinct signals. Pioneer neurons we identify, with unique growth properties, anatomy, and innervation, cooperate with glia to guide follower axons. We identified a CHIN-1/Chimaerin- KPC-1/Furin double mutant that severely disrupts assembly, unlike previously known mutants. CHIN-1/Chimaerin and KPC-1/Furin cooperate non-canonically in glia and pioneer neurons for guidance-cue trafficking. We exploit this genetic bottleneck to define a guidance-gene network governing assembly, with specific glia and pioneer-neuron contributions. Our studies reveal previously-unknown roles for glia in pioneer-axon guidance, and suggest conserved principles of brain formation.
Thursday December 8th - 14:00 – Salle Guillermond, Bâtiment L'Herbier, 9 rue Raphaël Dubois
Institut des Neurosciences Paris-Saclay, CNRS UMR 9197, Gif-sur-Yvette. France.
Neural crest in forebrain development: from embryology to pathophysiology
Invité par Valérie Castellani
In my group, we study the neural crest, a unique cell population that emerges from the primitive neural field and which has a multi-systemic and structural contribution to vertebrate development. Over the last decade, I have been dedicating myself to the cellular and molecular background of the observation I made in 2004, that the cephalic neural crest (CNC), exerts an autonomous and prominent control on forebrain development. This notion has broken the traditional view of how the brain develops. By using exquisite grafting experiments in combination with focal spatially and temporally controlled transgenesis, we have discovered the unexpected and potent “paracrine role that the CNC exerts on forebrain growth and patterning early in development and documented this mechanism at the level of cell interaction, signalling and gene expression. We are now following this exiting line of research, which revisits fundamental concepts in Neurosciences. This notion provides also a conceptual renewal, which is biomedically relevant. The mechanisms identified so far in our model are conserved across tetrapodes, but some social behavioural features are specific to amniotes. Our ongoing project and future directions are to explore the aetiology of neural disorders and behavioural impairments in Humans and in the light of CNC dysfunctions.
Monday November 14th at 11:00 – Salle Guillermond, Bâtiment L'Herbier, 9 rue Raphaël Dubois
Department of Human Genetics, McGill University - Québec, Canada.
Translational Control of Muscle Stem Cells
Invited by Rémi Mounier
Regeneration of adult tissues depends on somatic stem cells that remain quiescent, yet are primed to enter a differentiation program. The molecular pathways that prevent activation of these cells are not well understood. Using mouse skeletal muscle stem cells as a model, we show that accumulating transcripts specifying the myogenic program are not translated in quiescent satellite cells, but are repressed by the action of microRNAs and RNA binding proteins. Furthermore, the reversible nature of microRNA dependent silencing mechanisms may underlie the rapid activation of satellite cells that are poised to enter the myogenic program. We also show that a general repression of translation, mediated by the phosphorylation of translation initiation factor eIF2 at serine 51 (P-eIF2α), is required to maintain the quiescent state. Skeletal muscle stem cells unable to phosphorylate eIF2 exit quiescence, activate the myogenic program and differentiate, but do not self-renew. P-eIF2α ensures in part the robust translational silencing of accumulating mRNAs that is needed to prevent the activation of muscle stem cells. Additionally, P-eIF2α dependent translation of mRNAs regulated by upstream open reading frames (uORFs) contributes to the molecular signature of stemness. Finally, we show that addition of small molecule inhibitors of eIF2α dephosphorylation to muscle stem cell cultures permits their ex vivo expansion and engraftment into a preclinical mouse model of Duchenne muscular dystrophy.
Thursday November 17th at 11:00 – Amphithéâtre CNRS
Michael A Rudnicki
Center of Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
Molecular regulation of muscle stem cell asymmetric division
Invited by Bénédicte Chazaud
We discovered that a subset of satellite cells in skeletal muscle are self-renewing stem cells that give rise to myogenic progenitors through asymmetric apical-basal cell divisions. The regulation of asymmetric stem cell division is a key control point that impacts the efficacy of the entire regenerative program. Stem cell polarity is established by the PAR complex, comprised of PAR3/PAR6/aPKC, to regulate self-renewal and expansion. Duchenne Muscular Dystrophy (DMD) is coaused by a lack of dystrophin which is expressed in muscle fibers where it plays a role in ensuring structural integrity. We have made the seminal finding that dystrophin regulates the establishment of PAR-mediated polarity in satellite cells. In the absence of dystrophin, the polarity effector Par1b is dysregulated, leading to the failure of Par3 to become localized to the cortex associated with the basal lamina. Importantly, this results in an abnormal increase in centrosome number, a 10-fold reduction in the numbers of satellite stem cells undergoing asymmetric divisions, and a marked decrease in the generation of myogenin-expressing progenitors. Accordingly, our data suggests that the failure of regenerative myogenesis to keep pace with disease progression in DMD is not due to muscle stem cell exhaustion, but rather is due to a cell-autonomous deficiency in asymmetric division.
Tuesday November 22th at 14:00 – Amphithéâtre CNRS
F. Jeffrey Dilworth
Center of Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
Epigenetic control of stem cell fate decisions in muscle repair
Invited by Bénédicte Chazaud
During muscle regeneration, the conversion of muscle stem cells to terminally differentiated myofibers requires multiple cell fate transitions. Each of these transitions necessitates an alteration in the set of genes being expressed within the cell. In this presentation, our studies on the role of transcription factors and epigenetic enzymes in dictating changes in muscle gene expression will be highlighted. In particular, I will focus on the role for the antagonism between various transcription factors and epigenetic enzymes in controlling the commitment of muscle stem cells towards alternate cell fates.
Friday October 21st at 11:00 – Amphithéâtre CNRS
Fabien Le Grand
Center of Research in Myology, Université Pierre et Marie Curie Paris - France.
Control of muscle stem cell fate by Wnt signaling pathway(s)
Invited by Bénédicte Chazaud
Regeneration of the adult skeletal muscle tissue relies on a pool of quiescent muscle stem cells located in a niche around the myofibers: the satellite cells (MuSCs). Upon activation following injury or repeated exercise, MuSCs leave quiescence to proliferate and then differentiate to form new muscle fibers while a sub-population exit the cell cycle to self-renew and replenish the stem cell niche. In the course of this process, signals from the microenvironment instruct cycling MuSCs and control myogenesis. We previously demonstrated that numerous Wnt molecules are secreted in the local milieu during regeneration and showed that MuSC self-renewal is in part controlled by non-canonical Wnt7a/PCP signals sent by the regenerating myofibers. To elucidate the roles of the canonical Wnt/ß-catenin pathway in MuSCs, we generated mice with inducible MuSC-specific ß-catenin Loss-Of-Function or Gain-Of-Function. Strikingly, we observed that induction of either ß-catenin LOF or GOF mutations in MuSCs leads to the impairment of skeletal muscle regeneration following injury. By using a mouse model of conditional APC gene deletion in MuSCs we further demonstrated that the massive activation of canonical Wnt signaling in MuSC following APC loss results in defective cell cycle progression and apoptosis. Mechanistically, we observed that Wnt/ß-catenin signaling orchestrates the cytoplasmic relocalization of the histone 3 lysine 9 methyltransferase Setdb1 during differentiation. We further showed that Setdb1 is required for MuSCs amplification and suppresses myoblast terminal differentiation. Genome-wide analyses showed a Wnt3a-dependant release of Setdb1 from the promoter of selected target genes upon myoblast terminal differentiation. Taken together, our results demonstrate that both canonical and non-canonical Wnt pathways are necessary for MuSC function. Lastly, I will discuss the potential cross-talks between these two faces of an important signaling.
Wednesday October 5th at 11:00 – Salle Guillermond, Bâtiment L'Herbier, 9 rue Raphaël Dubois
Institut Albert Bonniot, Centre de Recherche UGA – INSERM U1209 / CNRS UMR 5309, Grenoble, France.
Epigenetic strategies : nucleosome remodeling, histone modifications and histone variants.
Invited by Laurent Schaeffer
Chromatin impedes the binding of protein factors to the underlying DNA sequences. The cell uses three main “epigenetic tools” to overcome the chromatin barrier, namely, chromatin remodelers, histone variants and histone post-translational modifications. We will give specific examples of how either one of these “epigenetic tools” functions.
Chromatin remodelers are sophisticated nano-machines, which are able to alter histone-DNA interactions and to mobilize nucleosomes. Neither the mechanism of their action nor the conformation of the remodeled nucleosomes are, however, yet well understood. We have studied the mechanism of RSC-induced chromatin remodeling by using high resolution microscopy and state of the art biochemistry techniques. The data illustrates how RSC remodels the nucleosome in vitro and shed light on its in vivo function. The crystal structure of the CENP-A nucleosome was recently solved. Intriguingly, in contrast to the canonical nucleosome (where 147 bp of DNA are wrapped around the histone octamer), only the central 121 bp were visible, suggesting flexible CENP-A nucleosomal ends. Why the CENP-A nucleosome exhibits flexible DNA ends is totally unknown. Our data show that the flexible DNA ends of the CENP-A nucleosome are required for mitotic fidelity.
The Aurora family of oncogenic kinase consists of two major members, Aurora A and Aurora B. Both kinases exhibit very high homology. They show, however, quite distinct localization and function. Histone H3 is specifically phosphorylated, presumably by the oncogenic kinase Aurora B, at serine 10 at the onset of mitosis. Here we will present data on the distinct function of the two Aurora kinases and the mechanism of phosphorylation of histone H3 by Aurora B.
Friday October 7th at 14:00 – Amphithéâtre CNRS
Institut de Myologie, UMRS 974 UPMC-Inserm / FRE 3617 CNRS, G. H. Pitié-Salpétrière, Paris - France.
The endocytic machinery in healthy and diseased muscle
Invited by Laurent Schaeffer
Costameres represent specialized focal adhesion sites of muscle fibres, located between the plasma membrane and sarcomeres, the contractile units of muscle. When disrupted, they directly contribute to the development of several distinct myopathies.
We have shown that the ubiquitous clathrin heavy chain (CHC), well characterized for its role in intracellular membrane traffic and endocytosis from the plasma membrane (PM), forms large plaques connected to α-actinin and actin filaments. Depletion of CHC leads to defective costamere formation and maintenance both in vitro and in vivo and induces sarcomere disorganization and a loss of contractile force due to the detachment of sarcomeres from the PM. At costameres, CHC is co-expressed with dynamin 2 (DNM2), another key protein of the intracellular membrane trafficking machinery which is mutated in autosomal dominant centronuclear myopathy (CNM). We analyzed the role of DNM2 and several actin binding proteins on clathrin plaque function at costameres in vitro by using either siRNA depletion combined to high resolution electron microscopy or in vivo by intravital microscopy. We also focused on the possible link between costamere and CNM pathophysiology. Using myoblasts from DNM2-mutated patients and using myoblasts and muscles from a knock-in mouse model of DNM2-related myopathy, we analyzed structure of costameres by biochemical and immunocytochemical approaches, as well as their ultrastructure.
Our results demonstrate a crucial role for the endocytic machinery and the cytoskeleton. Their contribution to the formation and maintenance of the contractile apparatus highlight an unconventional role for clathrin flat lattices in skeletal muscle which may be relevant to pathophysiology of several neuromuscular disorders.
Friday September 30th at 11:00 – Amphithéâtre CNRS
Huntingtin regulates cortical development: consequences for Huntington’s disease
Invited by Julien Courchet
The bulk of interest in the huntingtin protein has centered on the fact that, when mutated, huntingtin causes Huntington’s disease (HD), a devastating neurodegenerative disorder. The mutation causing HD is an abnormal polyglutamine stretch in huntingtin. Given the adult onset and dysfunction and death of adult neurons characterizing HD, most studies have focused on the toxic effects elicited by mutant huntingtin in post-mitotic neurons. However, the protein is ubiquitous and expressed in the developing embryo where it plays an essential role as revealed by the early embryonic lethality at day 7.5 of the complete knockout of the huntingtin gene in mouse. Anyway, the roles of the wild-type protein during development have been overlooked. I will discuss how huntingtin regulates several steps of mouse embryonic corticogenesis. I will also show the consequences of the presence of an abnormal polyglutamine expansion in huntingtin during cortical neurogenesis and consider the viewing of HD as a developmental disorder.
Tuesday July 12th at 11:00 – Amphithéâtre CNRS
Institute of Comparative Molecular Endocrinology
Ulm University, Ulm, Germany.
Modes of GR action revised – Novel mechanisms of corticosteroids in inflammation and bone integrity
Invited by Bénédicte Chazaud
The Tuckerman Laboratory made major contributions to the molecular mechanisms of corticosteroids in beneficial and side effects of steroid therapy. With the help of conditional and function-selective knockout mice for the glucocorticoid receptor (GR) the lab identified critical cell types and novel mechanisms for anti-inflammatory activities of glucocorticoids in different inflammatory disease models. Furthermore we made the discovery that in a model of lung inflammation the anti-inflammatory action of glucocorticoids is not dependent on the inhibition of pro-inflammatory mediators, but rather requires cooperation with pro-inflammatory signaling pathways (e.g. p38) to induce anti-inflammatory acting genes and alternative polarization of macrophages.
Friday June 24th at 14:00 – Salle Guillermond – Bâtiment l'Herbier
Dr. Pierre-Jean Corringer
Pasteur Institute, Channel-receptor Unit, CNRS UMR 3571, 25 rue du Docteur Roux, 75015 Paris, France.
Pentameric ligand-gated ion channels functioning at the atomic resolution
Invited by Maëlle Jospin
Pentameric channel-receptors, including nicotinic acetylcholine, glycine and GABAA receptors, play a key role in fast excitatory and inhibitory transmission in the nervous system and are the target of numerous therapeutic and addictive drugs. They carry several neurotransmitter binding sites which govern the opening of a transmembrane ion channel. Extensively expressed in animals, they were found in several bacteria, especially the homolog from the cyanobacteria Gloeobacter violaceus (GLIC) which functions as a proton-gated ion channel. The simplified architecture of this archaic homologue, as well as its prokaryotic origin, allowed solving its X-ray structure in several conformations. Those static structures suggest that channel opening occurs through symmetrical quaternary twist and “blooming” motions, together with tertiary deformation. We further engineered multiple fluorescent reporters on the structure, allowing investigating the dynamics of the allosteric reorganizations and showing that activation involves a key pre-active conformation. Finally, the GLIC system was exploited to solve the structure of human receptors through the generation of functional chimeras. Overall, our work gives insights into the mechanism of gating and pharmacological regulation of this important family of neurotransmitter receptors.
Monday May 30th at 14:00 – Salle Guillermond – Bâtiment l'Herbier
Dr. Yishi Jin
UC San Diego.
Mechanisms regulating synapse maintenance and neural activity
Invited by Jean-Louis Bessereau
Synapses are organized subcellular structures that transmit information within the nervous system and to other parts of our body. Our studies use C. elegans have uncovered multiple pathways controlling synapse formation, maintenance and function. Using a genetic model mimicking the physiological state of seizures, our recent work have identified novel regulatory themes affecting presynaptic release machinery. We also discovered that a novel immunoglobulin superfamily (IgSF) transmembrane protein mediates synapse and non-neuronal tissue interaction in synapse maintenance. These findings have implications to our understanding of circuit malfunction under disease conditions.
Thursday May 26th at 11:00 – Salle Guillermond – Bâtiment l'Herbier
Dr. Francesco Zorzato
Department of Biomedicine, Basel University
Pathophysiology of ryanodinopathies
Invited by Bruno Allard
Type 1 ryanodine receptor (RyR1) is preferentially expressed in skeletal muscle, and mutations in the gene have been associated with malignant hyperthermia, a pharmacogenetic disease, and with several congenital myopathies, including central core disease, multiminicore disease, centronuclear myopathy, congenital fibre type disproportion. Experimental data have indicated that RyR1 is also expressed in some areas of the central nervous system, in some cell types of the immune system and in smooth muscle cells. These results imply that mutations in the gene encoding RyR1 will not only affect skeletal muscles, but other tissues that express this calcium channel as well, thereby broadening the clinical spectrum of disorders due to RyR1 dysfunctions.
The RyR1 is of fundamental importance for the development of muscle force and a decrease in its content may be causally linked to the profound muscle weakness seen in patients with some forms of congenital myopathies linked to recessive RYR1 mutations. The protein composition of the junctional sarcoplasmic reticulum membrane encompassing the excitation-contraction coupling molecular complex (ECCMC) is extremely complicated. Polymorphic variants of the junctional sarcoplasmic reticulum protein JP45 have been shown to segregate in Malignant Hyperthermia Susceptible subjects of Malignant Hyperthermia families in the UK. Thus, some ECCMC accessory proteins may play a role not only in regulating excitation-contraction coupling but also as modifiers of the ryanodinopathies phenotype.
Thursday May 19th at 11:00 – Amphithéâtre de la délégation du CNRS
Dr. Jean-Marc Goaillard
UNIS - Aix Marseille Université
Biophysical networks underlying electrical phenotype of dopaminergic neurons
Invited by Thomas Boulin
Any type of neurons can be easily identified based on its electrophysiological activity, such as its pattern of spontaneous activity, the shape of its action potential, its dendritic integration, etc. How is stability of such electrical phenotype achieved, what are its molecular principles, and what is the degree of robustness of electrical phenotype in the face of different perturbations are questions only very partially answered. We studied these questions on dopaminergic neurons of the substantia nigra pars compacta. Our work involved characterizing the electrical phenotype of these neurons and measuring its post-natal development and its stability at mature stages. We also characterized the specific relationships of electrophysiological parameters underlying the electrical phenotype. In order to determine how complex electrical phenotype is achieved, we then investigated the networks of co-regulation of ion channels at the genetic and at the protein levels. Our results suggest that ion channel gene expression and protein interactions display a modular structure that may be involved in stabilizing phenotype. We also show that electrical phenotype also presents such a modular structure. Our ultimate goal is to provide a systems-level approach to robustness of electrical phenotype.
Friday 13th at 14:00 – Salle Guillermond – Bâtiment l'Herbier
Dr. Michele Zoli
Friday April 29th at 14:00 – Amphithéâtre de la délégation du CNRS
Dr. Shiva Tyagarajan
Inst. of Pharmacology and Toxicology, University of Zurich.
Interrupting neuronal communication from a GABAergic viewpoint
Invited by Jean-Louis Bessereau
In the brain distinct population of inhibitory GABAergic interneurons innervate principal glutamatergic neurons to regulate various aspects of brain function. At the postsynaptic compartment, specific GABAAR subunits are segregated to different neuronal compartments to recieve specific inputs from different interneurons. The correct interpretation of the incoming signal requires functional coupling between the presynaptic neurotransmitter GABA, postsynaptic GABAARs, and downstream signaling by postsynaptic density proteins. The main postsynaptic density protein at inhibitory synapse is gephyrin. In the past decade we have identified diverse signaling cascades that converge on gephyrin scaffold to regulate its scaffolding property, and in turn GABAergic neurotransmission. These studies have shed light into mechanisms that underlie dynamic changes in inhibitory neurotransmission, and how excitation shapes inhibition.
Friday Jan 29th at 14:00 – Bâtiment l'Herbier
ICREA Research Professor at Universitat Pompeu Fabra, Barcelona.
Tissue regenerative decline with aging: focus on muscle stem cells
Invited by Bénédicte Chazaud
Our group aims to understand the mechanisms regulating stem cell homeostasis and regenerative functions. Research is specially centered on stem cells of skeletal muscle (i.e., satellite cells). Recently, we have focused on two areas: 1) the functional decline of satellite cells with aging; and 2) the physiopathology of muscular dystrophies, with a specific interest in the contribution of inflammation and fibrosis to dystrophy progression. Concerning the first area, work from different laboratories has demonstrated that both environmental and cell- autonomous signals alter satellite cell regenerative potential with aging. I will discuss our latest results showing that satellite cells in their homeostatic quiescent state are equipped with quality control mechanisms to preserve their fitness, and how age-associate alterations in these protective mechanisms lead to stem cell loss of function and regenerative capacity.