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

Myostatin gene inactivation in a mouse model of cancer cachexia : involvement in the regulation of muscle mass

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 cachexi

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

Cachexia 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 cachexiaLa 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 cance

Confounding Roles of ER Stress and the Unfolded Protein Response in Skeletal Muscle Atrophy

International audienceSkeletal muscle is an essential organ, responsible for many physiological functions such as breathing, locomotion, postural maintenance, thermoregulation, and metabolism. Interestingly, skeletal muscle is a highly plastic tissue, capable of adapting to anabolic and catabolic stimuli. Skeletal muscle contains a specialized smooth endoplasmic reticulum (ER), known as the sarcoplasmic reticulum, composed of an extensive network of tubules. In addition to the role of folding and trafficking proteins within the cell, this specialized organelle is responsible for the regulated release of calcium ions (Ca2+) into the cytoplasm to trigger a muscle contraction. Under various stimuli, such as exercise, hypoxia, imbalances in calcium levels, ER homeostasis is disturbed and the amount of misfolded and/or unfolded proteins accumulates in the ER. This accumulation of misfolded/unfolded protein causes ER stress and leads to the activation of the unfolded protein response (UPR). Interestingly, the role of the UPR in skeletal muscle has only just begun to be elucidated. Accumulating evidence suggests that ER stress and UPR markers are drastically induced in various catabolic stimuli including cachexia, denervation, nutrient deprivation, aging, and disease. Evidence indicates some of these molecules appear to be aiding the skeletal muscle in regaining homeostasis whereas others demonstrate the ability to drive the atrophy. Continued investigations into the individual molecules of this complex pathway are necessary to fully understand the mechanisms

Molecular mechanisms of cancer cachexia‐related loss of skeletal muscle mass: data analysis from preclinical and clinical studies

Abstract Cancer cachexia is a systemic hypoanabolic and catabolic syndrome that diminishes the quality of life of cancer patients, decreases the efficiency of therapeutic strategies and ultimately contributes to decrease their lifespan. The depletion of skeletal muscle compartment, which represents the primary site of protein loss during cancer cachexia, is of very poor prognostic in cancer patients. In this review, we provide an extensive and comparative analysis of the molecular mechanisms involved in the regulation of skeletal muscle mass in human cachectic cancer patients and in animal models of cancer cachexia. We summarize data from preclinical and clinical studies investigating how the protein turnover is regulated in cachectic skeletal muscle and question to what extent the transcriptional and translational capacities, as well as the proteolytic capacity (ubiquitin–proteasome system, autophagy–lysosome system and calpains) of skeletal muscle are involved in the cachectic syndrome in human and animals. We also wonder how regulatory mechanisms such as insulin/IGF1–AKT–mTOR pathway, endoplasmic reticulum stress and unfolded protein response, oxidative stress, inflammation (cytokines and downstream IL1ß/TNFα–NF‐κB and IL6–JAK–STAT3 pathways), TGF‐ß signalling pathways (myostatin/activin A‐SMAD2/3 and BMP‐SMAD1/5/8 pathways), as well as glucocorticoid signalling, modulate skeletal muscle proteostasis in cachectic cancer patients and animals. Finally, a brief description of the effects of various therapeutic strategies in preclinical models is also provided. Differences in the molecular and biochemical responses of skeletal muscle to cancer cachexia between human and animals (protein turnover rates, regulation of ubiquitin‐proteasome system and myostatin/activin A‐SMAD2/3 signalling pathways) are highlighted and discussed. Identifying the various and intertwined mechanisms that are deregulated during cancer cachexia and understanding why they are decontrolled will provide therapeutic targets for the treatment of skeletal muscle wasting in cancer patients

Editorial: Emerging Mechanisms for Skeletal Muscle Mass Regulation

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Effect of Denervation on XBP1 in Skeletal Muscle and the Neuromuscular Junction

International audienceDenervation of skeletal muscle is a debilitating consequence of injury of the peripheral nervous system, causing skeletal muscle to experience robust atrophy. However, the molecular mechanisms controlling the wasting of skeletal muscle due to denervation are not well understood. Here, we demonstrate that transection of the sciatic nerve in Sprague–Dawley rats induced robust skeletal muscle atrophy, with little effect on the neuromuscular junction (NMJ). Moreover, the following study indicates that all three arms of the unfolded protein response (UPR) are activated in denervated skeletal muscle. Specifically, ATF4 and ATF6 are elevated in the cytoplasm of skeletal muscle, while XBP1 is elevated in the nuclei of skeletal muscle. Moreover, XBP1 is expressed in the nuclei surrounding the NMJ. Altogether, these results endorse a potential role of the UPR and, specifically, XBP1 in the maintenance of both skeletal muscle and the NMJ following sciatic nerve transection. Further investigations into a potential therapeutic role concerning these mechanisms are needed

Exercise-specific effects on the motor performance, glycemia regulation and muscle histology of a mouse model of limb-girdle muscular dystrophy r1 (calpainopathy)

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Exercise-specific effects on the motor performance, glycemia regulation and muscle histology of a mouse model of limb-girdle muscular dystrophy r1 (calpainopathy)

International audienc

Effect of Denervation on XBP1 in Skeletal Muscle and the Neuromuscular Junction

Denervation of skeletal muscle is a debilitating consequence of injury of the peripheral nervous system, causing skeletal muscle to experience robust atrophy. However, the molecular mechanisms controlling the wasting of skeletal muscle due to denervation are not well understood. Here, we demonstrate that transection of the sciatic nerve in Sprague–Dawley rats induced robust skeletal muscle atrophy, with little effect on the neuromuscular junction (NMJ). Moreover, the following study indicates that all three arms of the unfolded protein response (UPR) are activated in denervated skeletal muscle. Specifically, ATF4 and ATF6 are elevated in the cytoplasm of skeletal muscle, while XBP1 is elevated in the nuclei of skeletal muscle. Moreover, XBP1 is expressed in the nuclei surrounding the NMJ. Altogether, these results endorse a potential role of the UPR and, specifically, XBP1 in the maintenance of both skeletal muscle and the NMJ following sciatic nerve transection. Further investigations into a potential therapeutic role concerning these mechanisms are needed