Apoptosis-Inducing Factor Regulates Skeletal Muscle Progenitor Cell Number and Muscle Phenotype

Apoptosis Inducing Factor (AIF) is a highly conserved, ubiquitous flavoprotein localized in the mitochondrial intermembrane space. In vivo, AIF provides protection against neuronal and cardiomyocyte apoptosis induced by oxidative stress. Conversely in vitro, AIF has been demonstrated to have a pro-apoptotic role upon induction of the mitochondrial death pathway, once AIF translocates to the nucleus where it facilitates chromatin condensation and large scale DNA fragmentation. Given that the aif hypomorphic harlequin (Hq) mutant mouse model displays severe sarcopenia, we examined skeletal muscle from the aif hypomorphic mice in more detail. Adult AIF-deficient skeletal myofibers display oxidative stress and a severe form of atrophy, associated with a loss of myonuclei and a fast to slow fiber type switch, both in “slow” muscles such as soleus, as well as in “fast” muscles such as extensor digitorum longus, most likely resulting from an increase of MEF2 activity. This fiber type switch was conserved in regenerated soleus and EDL muscles of Hq mice subjected to cardiotoxin injection. In addition, muscle regeneration in soleus and EDL muscles of Hq mice was severely delayed. Freshly cultured myofibers, soleus and EDL muscle sections from Hq mice displayed a decreased satellite cell pool, which could be rescued by pretreating aif hypomorphic mice with the manganese-salen free radical scavenger EUK-8. Satellite cell activation seems to be abnormally long in Hq primary culture compared to controls. However, AIF deficiency did not affect myoblast cell proliferation and differentiation. Thus, AIF protects skeletal muscles against oxidative stress-induced damage probably by protecting satellite cells against oxidative stress and maintaining skeletal muscle stem cell number and activation

Etude de l'implication de deux molécules dans la régénération du muscle squelettique chez la souris (un facteur de croissance, le FGF6 et une protéine du métabolisme anti-oxydant, AIF)

Nous avons étudié du rôle du FGF6 dans la régénération musculaire en caractérisant le phénotype du Tibialis Antérieur (non lésé et après régénération) de souris Fgf6-/- selon une approche histologique, immunohistochimique et fonctionnelle. Puis nous avons étudié le profil d expression spatio-temporel des gènes Spry (régulateurs négatifs de la voie de signalisation des FGFs) par des expériences de RT-PCR semi-quantitatives, en temps réel et par hybridations in situ. Ces analyses ont été menées sur des soleus de souris sauvages et Fgf6-/- en cours de régénération. Enfin, nous nous sommes intéressés à l effet du stress oxydant sur ce processus. Le modèle utilisé est la souris Harlequin, présentant une déficience en la protéine AIF impliquée dans la réduction du stress oxydant. Ainsi, les souris Harlequin sujettes à un important stress oxydant présentent un retard de régénération, une atrophie musculaire, une typologie musculaire plus lente et une altération du pool de cellules satellites.PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Early survival factor deprivation in the olfactory epithelium enhances activity-dependent survival

Early survival factor deprivation in the olfactory epithelium enhances activity-dependent survival. Colloque de clôture de l'IFR 144 NeuroSud-Pari

Modulation de la perception olfactive par l'endothéline

National audienc

Endothelin as a neuroprotective factor in the olfactory epithelium

International audienceIn mammals, the olfactory sensory neurons are the only ones directly in contact with an aggressive environment. Thus, the olfactory mucosa is one of the few neuronal zones which are continuously renewed during adulthood. We have previously shown that endothelin is locally matured in the olfactory mucosa and that olfactory sensory neurons preferentially express ET(B) receptors, while ET(A) receptors are rather present in non neuronal olfactory mucosa cells. In addition to its vasoactive effect, the endothelin system is known for its pleiotropic effects including the modulation of cell population dynamics. We thus examined its potential neuroprotective effect in the olfactory mucosa using a primary culture of olfactory sensory neurons lying on non neuronal cells. While a serum deprivation led to a massive decrease of the density of olfactory sensory neurons in the primary cultures, endothelin 1 (ET-1) rescued part of the neuronal population through both ET(A) and ET(B) receptors. This effect was mainly anti-apoptotic as it reduced cleaved caspase-3 signal and nuclear condensation. Furthermore, the olfactory epithelium of ET(B)-deficient rats displayed increased apoptosis. These results strongly suggest that ET-1 acts as an anti-apoptotic factor on olfactory sensory neurons, directly through ET(B) and indirectly by limiting non neuronal cells death through ET(A)

Insulin a survival factor for olfactory mucosa

National audienc

Coherence and Stochastic Dominance

National audienc

Insulin but not leptin protects olfactory mucosa from apoptosis

International audienceThe mammalian olfactory mucosa (OM) is continually renewed throughout life. Owing to their position in the nasal cavity, OM cells are exposed to multiple insults, including high levels of odourants that can induce their death. OM regeneration is therefore essential to maintain olfactory function, and requires the tight control of both cell death and proliferation. Apoptosis has been implicated in OM cell death. Olfaction is one of the senses involved in food intake and depends on individual nutritional status. We have previously reported the influence of hormones related to nutritional status on odour perception and have shown that the OM is a target of insulin and leptin, two hormones known for their anti-apoptotic properties. In the present study, we investigated the potential anti-apoptotic effect of these metabolic hormones on OM cells. Both Odora cells (an olfactive cell line) and OM cells treated with etoposide, a p53 activity inducer, exhibited mitochondrial-dependent apoptosis that was inhibited by the pan-caspase inhibitor zVAD-fmk. Insulin, but not leptin, impaired this apoptotic effect. Insulin addition to the culture medium reduced p53 phosphorylation, caspase-3 and caspase-9 cleavage, and caspase-3 enzymatic activity induced by etoposide. The apoptotic wave observed in the OM after interruption of the neuronal connections between the OM and the olfactory bulb by bulbectomy was impaired by intranasal insulin treatment. These findings suggest that insulin may be involved in OM cellular dynamics, through endocrine and/or paracrine-autocrine effects of circulating or local insulin, respectively

Endothelin modulates both short-term detection kinetics of odors and long-term cellular population dynamics in olfactory mucosa

International audienc