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Microcebus murinus, or gray mouse lemur (GML), is one of the smallest primates known, with a size in between mice and rats. The small size, genetic proximity to humans and prolonged senescence, make this lemur an emerging model for neurodegenerative diseases. For the same reasons, it could help understand how aging affects cardiac activity. Here, we provide the first characterization of sinoatrial (SAN) pacemaker activity and of the effect of aging on GML heart rate (HR). According to GML size, its heartbeat and intrinsic pacemaker frequencies lie in between those of mice and rats. To sustain this fast automaticity the GML SAN expresses funny and Ca2+ currents (If, ICa,L and ICa,T) at densities similar to that of small rodents. SAN automaticity was also responsive to β-adrenergic and cholinergic pharmacological stimulation, showing a consequent shift in the localization of the origin of pacemaker activity. We found that aging causes decrease of basal HR and atrial remodeling in GML. We also estimated that, over 12 years of a lifetime, GML generates about 3 billion heartbeats, thus, as many as humans and three times more than rodents of equivalent size. In addition, we estimated that the high number of heartbeats per lifetime is a characteristic that distinguishes primates from rodents or other eutherian mammals, independently from body size. Thus, cardiac endurance could contribute to the exceptional longevity of GML and other primates, suggesting that GML’s heart sustains a workload comparable to that of humans in a lifetime. In conclusion, despite the fast HR, GML replicates some of the cardiac deficiencies reported in old people, providing a suitable model to study heart rhythm impairment in aging. Moreover, we estimated that, along with humans and other primates, GML presents a remarkable cardiac longevity, enabling longer life span than other mammals of equivalent size.

International audience; Statement of the Problem: Pancreatic beta cells are unique effectors in the control of glucose homeostasis and their deficiency results in impaired insulin production leading to severe diabetic diseases. Here, we investigated the potential of a population of non-adherent Muscle-Derived Stem Cells (MDSC) from adult mouse or human muscle to differentiate in vitro into beta cells and when transplanted in vivo, as undifferentiated stem cells, differentiate in vivo and compensate for beta cell deficiency. Methodology & Theoretical Orientation: In vitro, MDSC were isolated on the basis of their poor adherence by serial preplating for 8 days. MDSC cultured for several weeks, spontaneously differentiated into insulin-expressing islet-like cell clusters as revealed using MDSC from transgenic mice expressing GFP or mCherry under the control of an insulin promoter. Differentiated clusters of beta-like cells co-expressed insulin with the transcription factors Pdx1, Nkx2.2, Nkx6.1 and MafA, and secreted significant levels of insulin in response to glucose challenges. In vivo, undifferentiated MDSC injected intraperitoneal into streptozotocin (STZ)-treated mice, engrafted within 48h specifically into damaged pancreatic islets and are shown to differentiate and express insulin 2-12 days after injection. In addition injection of MDSC to hyperglycemic diabetic STZ treated mice reduced their blood glucose levels for 2 to 10 weeks. Conclusion & Significance: These data show that muscle stem cells, MDSC, are capable of differentiating into mature pancreatic beta islet-like cells not only upon culture in vitro but also in vivo after systemic injection in STZ-induced diabetic mouse models. Being non teratogenic, MDSC can be used directly by systemic injection and this potential reveals a promising alternative avenue in stem cell-based treatment of beta cell deficiencies. ; Ned Lamb et al., Endocrinol Diabetes Res 2019, Volume 05; Exposé du problème: Les cellules bêta du pancréas sont des effecteurs uniques dans le contrôle de l'homéostasie du glucose et leur carence entraîne une production insuffisante d'insuline menant à de graves maladies du diabète. Ici, nous avons étudié le potentiel d’une population de cellules souches dérivées des muscles non adhérentes (MDSC) provenant de muscles de souris ou humains adultes à se différencier in vitro en cellules bêta et lorsqu’une greffe in vivo, en tant que cellules souches indifférenciées, différencie in vivo et compense pour le déficit en cellules bêta. Méthodologie et orientation théorique: In vitro, les CDEM ont été isolés sur la base de leur faible adhérence par prélaquage en série pendant 8 jours. MDSC en culture pendant plusieurs semaines, spontanément différenciée en grappes de cellules ressemblant à des îlots exprimant l'insuline, révélée à l'aide de MDSC provenant de souris transgéniques exprimant la GFP ou mCherry sous le contrôle d'un promoteur de l'insuline. Des groupes différenciés de cellules de type bêta co-exprimaient l'insuline avec les facteurs de transcription Pdx1, Nkx2.2, Nkx6.1 et MafA, et sécrétaient des taux importants d'insuline en réponse à des problèmes de glucose. MDSC non différenciée in vivo, injectée par voie intrapéritonéale à des souris traitées à la streptozotocine (STZ), greffée 48 heures plus tard dans des îlots pancréatiques endommagés, et capable de différencier et d'exprimer l'insuline 2 à 12 jours après l'injection. De plus, l'injection de MDSC à des souris hyperglycémiques diabétiques traitées à la STZ a réduit leur glycémie pendant 2 à 10 semaines. Conclusion et signification: Ces données montrent que les cellules souches musculaires, MDSC, sont capables de se différencier en cellules matures ressemblant à des îlots bêta du pancréas, non seulement lors d'une culture in vitro, mais également in vivo après une injection systémique chez des modèles de souris diabétiques induites par STZ. Étant non tératogène, le MDSC peut être utilisé directement par injection systémique et ce potentiel révèle une alternative prometteuse dans le traitement par cellules souches des carences en cellules bêta. ; Ned Lamb et al., Endocrinol Diabetes Res 2019, Volume 05

Kinases of the Akt family are integral and essential components in growth factor signaling pathways activated downstream of the membrane bound phospho-inositol-3 kinase. In light of strong homologies in the primary amino acid sequence, the three Akt kinases were long surmised to play redundant and overlapping roles in insulin signaling across the spectra of cell and tissue types. Over the last 10 years, work using mouse knockout models, cell specific inactivation, and more recently targeted gene inactivation, has brought into question the redundancy within Akt kinase isoforms and instead pointed to isoform specific functions in different cellular events and diseases. Here we concentrate on the differential roles played by Akt1 and Akt2 in a variety of cellular processes and in particular during cancer biogenesis. In this overview, we illustrate that while Akt1 and 2 are often implicated in many aspects of cellular transformation, the two isoforms frequently act in a complementary opposing manner. Furthermore, Akt1 and Akt2 kinases interact differentially with modulating proteins and are necessary in relaying roles during the evolution of cancers from deregulated growth into malignant metastatic killers. These different actions of the two isoforms point to the importance of treatments targeting isoform specific events in the development of effective approaches involving Akt kinases in human disease.