The Translation Regulatory Subunit eIF3f Controls the Kinase-Dependent mTOR Signaling Required for Muscle Differentiation and Hypertrophy in Mouse

The mTORC1 pathway is required for both the terminal muscle differentiation and hypertrophy by controlling the mammalian translational machinery via phosphorylation of S6K1 and 4E-BP1. mTOR and S6K1 are connected by interacting with the eIF3 initiation complex. The regulatory subunit eIF3f plays a major role in muscle hypertrophy and is a key target that accounts for MAFbx function during atrophy. Here we present evidence that in MAFbx-induced atrophy the degradation of eIF3f suppresses S6K1 activation by mTOR, whereas an eIF3f mutant insensitive to MAFbx polyubiquitination maintained persistent phosphorylation of S6K1 and rpS6. During terminal muscle differentiation a conserved TOS motif in eIF3f connects mTOR/raptor complex, which phosphorylates S6K1 and regulates downstream effectors of mTOR and Cap-dependent translation initiation. Thus eIF3f plays a major role for proper activity of mTORC1 to regulate skeletal muscle size

Effets de polysaccharides sulfatés sur la différenciation des cellules endothéliales humaines

PARIS13-BU Sciences (930792102) / SudocSudocFranceF

New insights into myostatin function in muscle protein homeostasis highlight a link with the regulation of translation ght

New insights into myostatin function in muscle protein homeostasis highlight a link with the regulation of translation gh

New insights into myostatin function in muscle protein homeostasis highlight a link with the regulation of translation ght

New insights into myostatin function in muscle protein homeostasis highlight a link with the regulation of translation gh

New insights into myostatin function in muscle protein homeostasis highlight a link with the regulation of translation ght

New insights into myostatin function in muscle protein homeostasis highlight a link with the regulation of translation gh

Impact de génotypes musculaires sur les caractéristiques fonctionnelles et métaboliques du muscle in vivo

Impact de génotypes musculaires sur les caractéristiques fonctionnelles et métaboliques du muscle in vivo. Journées d’Animation des Crédits Incitatifs du Département de Physiologie Animale et Systèmes d’Elevage (JACI Phase 2016

Myostatin inactivation increases myotube size through regulation of translational initiation machinery

International audienceMyostatin deficiency leads in skeletal muscle overgrowth but the precise molecular mechanisms underlying this hypertrophy are not well understood. In this study, to gain insight into the role of endogenous myostatin in the translational regulation, we used an in vitro model of cultured satellite cells derived from myostatin knock-out mice. Our results show that myostatin knock-out myotubes are larger than control myotubes and that this phenotype is associated with an increased activation of the Akt/mTOR signaling pathway, a known regulator of muscle hypertrophy. These results demonstrate that hypertrophy due to myostatin deficiency is preserved in vitro and suggest that myostatin deletion results in an increased protein synthesis. Accordingly, the rates of global RNA content, polysome formation and protein synthesis are all increased in myostatin-deficient myotubes while they are counteracted by the addition of recombinant myostatin. We furthermore demonstrated that genetic deletion of myostatin stimulates cap-dependent translation by positively regulating assembly of the translation preinitiation complex. Together the data indicate that myostatin controls muscle hypertrophy in part by regulating protein synthesis initiation rates, that is, translational efficiency

Impact de génotypes musculaires sur les caractéristiques fonctionnelles et métaboliques du muscle in vivo

Impact de génotypes musculaires sur les caractéristiques fonctionnelles et métaboliques du muscle in vivo. Journées d’Animation des Crédits Incitatifs du Département de Physiologie Animale et Systèmes d’Elevage (JACI Phase 2016

Evidence for autophagy attenuation during post-mortem maturation of hypertrophied muscle in myostatin deficient mice

International audienceThe conversion of skeletal muscle into meat, i.e. maturation, is a complex process where muscle undergoes different biochemical and physiological changes. In agronomic field, the study of these events is of particular interest, in order to improve the quality of the final product put on the market. If the characterization of the proteolytic mechanisms involved in skeletal muscle maturation is still ongoing, the participation of autophagy in this process is still under debate.In order to decipher the involvement of autophagy during skeletal muscle maturation, the expression and activation of keys proteins regulating this process have been followed within a 48h postmortem (PM) time frame in mice. The interaction between autophagy and myostatin, a negative regulator of skeletal muscle mass, was also analyzed during this post-mortem interval.Using 6 month-old wild-type (WT) and myostatin knocked-out (Mstn KO) mice, we measured the proteolysis of myofibrillar proteins (filamin and troponin T), as well as the activation and expression of proteins involved in autophagic pathway (AMPK, FOXO, ULK, LC3 and p62).Our results showed a progressive degradation of myofibrillar proteins over the 48h PM period. Moreover, it was more pronounced in gastrocnemius muscle of Mstn KO mice when compared to WT mice. AMPK activation was more marked in WT mice, with a maximal induction between 2 and 4h PM, suggestive of an energetic stress. Inhibition of Foxo1 phosphorylation (Thr24) was relieved in the late PM interval (8h PM) in both genotypes, indicating the activation of proteolytic pathways. Concerning autophagy, the phosphorylation profile of ULK1 (Ser757 vs Ser555) suggests an early activation (1h PM) of autophagy in Mstn KO mice. To estimate the autophagic flux, LC3 and p62 protein expression were measured after autophagy blockade with colchicine at 0h, 4h, 8h and 24h postmortem. Our results showed a higher flux in the WT mice compared to Mstn KO mice, whatever the PM time.In conclusion, our data showed that autophagy is maintained during skeletal muscle PM maturation, but to a lower extent in Mstn-deficient mice, suggesting a relationship between myostatin and autophagy