Myostatin in the Pathophysiology of Skeletal Muscle

Myostatin is an endogenous, negative regulator of muscle growth determining both muscle fiber number and size. The myostatin pathway is conserved across diverse species ranging from zebrafish to humans. Experimental models of muscle growth and regeneration have implicated myostatin as an important mediator of catabolic pathways in muscle cells. Inhibition of this pathway has emerged as a promising therapy for muscle wasting. Here we discuss the recent developments and the controversies in myostatin research, focusing on the molecular and cellular mechanisms underlying the actions of myostatin on skeletal muscle and the potential therapeutic role of myostatin on muscle-related disorders

Invalidation du gène de la myostatine dans un modèle murin de cachexie associée au cancer (implication dans la régulation de la masse musculaire)

La cachexie est un syndrome clinique et métabolique caractérisé par une perte de tissu adipeux et de tissu musculaire, fréquemment observé chez les patients atteints de cancer. La myostatine (Mstn) régule négativement la masse musculaire. Bien que la régulation des mécanismes moléculaires impliqués dans le contrôle de la masse musculaire joue un rôle central dans la cachexie associée au cancer, les relations existant entre la Mstn et les mécanismes physiopathologiques restent largement inconnues. Suite à l inoculation de cellules Lewis lung carcinoma (LLC) à des souris, nous avons montré que l invalidation du gène de la Mstn (souris Mstn-/-) confère une résistance au développement de la cachexie associée au cancer par rapport à des souris sauvages. La déficience en Mstn prévient la perte de masse musculaire et réduit la croissance tumorale, 35 jours après l injection des cellules LLC, et est associée à un allongement de la durée de vie des souris. L invalidation du gène de la Mstn provoque aussi une augmentation de l apoptose des cellules LLC et une diminution de l'expression de gènes impliqués dans la prolifération et le métabolisme tumoraux. L activation des systèmes protéolytiques ubiquitine-protéasome et autophagie-lysosome, due au développement tumoral, est réduite voire supprimée dans le muscle des souris Mstn-/-. L accumulation de céramides intramusculaires, un sphingolipide formé suite à une lipolyse exacerbée, est corrélée à la perte de masse musculaire, suggérant que les céramides pourraient être un médiateur cellulaire impliqué dans la cachexie associée au cancer. Ces résultats montrent que la Mstn joue un rôle essentiel dans la cachexie associée au cancerCachexia is a complex clinical and metabolic syndrome, whose definition is imprecise, characterized by an uncontrolled loss of adipose tissue and skeletal muscle mass, frequently observed in cancer patients, and leading to death in 25% of cancer patients. Myostatin (Mstn) is a negative regulator of skeletal muscle mass and a critical determinant of skeletal muscle homeostasis. Although the regulation of the molecular mechanisms involved in the control of skeletal muscle mass plays a central role in the pathogenesis of cancer cachexia, the relationships between Mstn and the pathophysiological mechanisms remain largely unknown. Following subcutaneous inoculation of Lewis lung carcinoma cells (LLC) in mice, we showed that the Mstn gene inactivation (Mstn-/- mice) confers resistance to the development of cancer cachexia, compared to wild type mice. Mstn deficiency prevents the loss of skeletal muscle mass and reduces tumor growth, 35 days after the inoculation of LLC cells, and this is associated with a longer life of mice. Mstn gene inactivation also causes an increased apoptosis of LLC cells and decreases expression of genes involved in tumor proliferation and metabolism. Activation of ubiquitin-proteasome and autophagy-lysosome proteolytic systems, triggered by tumor growth is significantly reduced or suppressed in skeletal muscle of Mstn-/- mice. Accumulation of intramuscular ceramides, a sphingolipid synthesized due to excessive lipolysis, is correlated with the loss of muscle mass, suggesting that ceramides may be a cellular mediator involved in the pathogenesis of cancer cachexia. These results show that Mstn plays a critical role in the pathogenesis of cancer cachexiaST ETIENNE-Bib. électronique (422189901) / SudocSudocFranceF

Role and Function of Wnts in the Regulation of Myogenesis: When Wnt Meets Myostatin

Chapter 4International audienc

Determinants structuraux de l'instabilite des messagers c-myc et c-fos

SIGLECNRS T Bordereau / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Le facteur d'initiation de la traduction eIF3f dans le muscle squelettique (étude in vitro et obtention de modèles animaux)

Le facteur d'initiation de la traduction eIF3f est une des sous-unités constituant le facteur d'initiation de la traduction eIF3. Au niveau musculaire la surexpression de eIF3f dans les myotubes induit une hypertrophie associée à une augmentation de la synthèse protéique. A l'inverse, l'inhibition de l'expression de eIF3f entraîne une atrophie associée à une diminution de la synthèse protéique. Ce travail de thèse a permis (i) in vitro de mettre en évidence les fonctions inhibitrices du facteur eIF3f au cours de la prolifération des myoblastes C2C12 et par une étude transcriptomique sur les fractions polysomales de caractériser les ARNm recrutés par eIF3f dans des conditions hypertrophiques; et (ii) de créer des lignées de souris inactivées pour eIF3f (souris KO eIF3f) et surexprimant eIF3f dans le muscle (souris transgénique eIF3f K5-10R) afin d'étudier in vivo l'impact de la modification de l'expression de eIF3f sur la régulation de la masse musculaire.The eukaryotic initiation factor eIF3f is one of the subunits of the translation initiator complex eIF3 required for several steps in the initiation of mRNA translation. In skeletal muscle, recent studies have demonstrated that eIF3f overexpression in myotubes exerts a hypertrophic activity associated to an increase in protein synthesis. This thesis shed light on muscle eIF3f functions by (i) characterizing in vitro the antiproliferative activity of this factor in C2C12 myoblasts and the RNAs recruited by eIF3f on polysomal fractions in hypertrophied myotubes and (ii) generating mice strains inactivated for eIF3f (eIF3f KO mice) and overexpressing eIF3f specifically in muscle (eIF3f K5-10R transgenic mice) to study in vivo the impact of eIF3f modulation on the muscular mass homeostasisMONTPELLIER-BU Médecine UPM (341722108) / SudocSudocFranceF

Requirements for c-fos mRNA down regulation in growth stimulated murine cells

International audienceThe fos proto-oncogene is rapidly and transiently expressed in resting cells exposed to growth stimulation. This gene is down-regulated at least at two levels: transcriptional repression and mRNA degradation. To determine the sequences and the structures involved in mRNA instability, we analyzed in mouse Ltk- cells various fos/beta-globin constructs for their transcriptional activity and the half-lives of the corresponding RNAs. In these cells, rabbit beta-globin genes under the control of a 500 bp fos SRE (serum responsive element)/promoter region are transiently transcribed within 30 min after stimulation. Analysis of the decay kinetics of RNA originating from these constructs led to the following conclusions with respect to the nature of c-fos destabilizer elements: (i) 100 bases from c-fos 3' untranslated region are able to confer instability when inserted into a normally stable beta-globin RNA; (ii) however, the degradation is more rapid when the complete untranslated region is inserted; (iii) rapid mRNA breakdown requires more determinants than two AUUUA motives and is associated with a reduction in size, presumably due to a poly(A) shortening; (iv) remarkably, c-fos destabilizing sequences remain active even when part of the coding sequence

Myostatin deficiency is associated with an increase in number of total axons and motor axons innervating mouse tibialis anterior muscle

Contact: [email protected] audienceINTRODUCTION: Myostatin (Mstn) is a secreted protein that acts as a negative regulator of skeletal muscle mass. However, a critical evaluation of neuromuscular aspects of hypertrophied muscles induced by Mstn deficiency has not been done. METHODS: We compared the tibialis anterior musclenerve interrelationships in wild-type and Mstn-null mice of both genders by immunohistochemical analyses, which allowed us to count the number of total axons and motor axons and estimate the size of motor units and the innervation ratio of the tibialis anterior muscle (TAm). RESULTS: There was an increase in the number of total axons and motor axons, and higher values in both the motor unit size and the innervation ratio of Mstn-null TAm compared with those of wild-type TAm. CONCLUSIONS: We found that myostatin is involved either directly in the control of neuromuscular interrelationships or indirectly through its effect on muscle size

Requirements for c-fos mRNA down regulation in growth stimulated murine cells

International audienceThe fos proto-oncogene is rapidly and transiently expressed in resting cells exposed to growth stimulation. This gene is down-regulated at least at two levels: transcriptional repression and mRNA degradation. To determine the sequences and the structures involved in mRNA instability, we analyzed in mouse Ltk- cells various fos/beta-globin constructs for their transcriptional activity and the half-lives of the corresponding RNAs. In these cells, rabbit beta-globin genes under the control of a 500 bp fos SRE (serum responsive element)/promoter region are transiently transcribed within 30 min after stimulation. Analysis of the decay kinetics of RNA originating from these constructs led to the following conclusions with respect to the nature of c-fos destabilizer elements: (i) 100 bases from c-fos 3' untranslated region are able to confer instability when inserted into a normally stable beta-globin RNA; (ii) however, the degradation is more rapid when the complete untranslated region is inserted; (iii) rapid mRNA breakdown requires more determinants than two AUUUA motives and is associated with a reduction in size, presumably due to a poly(A) shortening; (iv) remarkably, c-fos destabilizing sequences remain active even when part of the coding sequence

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