Specific shifts in the endocannabinoid system in hibernating brown bears

In small hibernators, global downregulation of the endocannabinoid system (ECS), which is involved in modulating neuronal signaling, feeding behavior, energy metabolism, and circannual rhythms, has been reported to possibly drive physiological adaptation to the hibernating state. In hibernating brown bears (Ursus arctos), we hypothesized that beyond an overall suppression of the ECS, seasonal shift in endocannabinoids compounds could be linked to bear's peculiar features that include hibernation without arousal episodes and capacity to react to external disturbance. We explored circulating lipids in serum and the ECS in plasma and metabolically active tissues in free-ranging subadult Scandinavian brown bears when both active and hibernating. In winter bear serum, in addition to a 2-fold increase in total fatty acid concentration, we found significant changes in relative proportions of circulating fatty acids, such as a 2-fold increase in docosahexaenoic acid C22:6 n-3 and a decrease in arachidonic acid C20:4 n-6. In adipose and muscle tissues of hibernating bears, we found significant lower concentrations of 2-arachidonoylglycerol (2-AG), a major ligand of cannabinoid receptors 1 (CB1) and 2 (CB2). Lower mRNA level for genes encoding CB1 and CB2 were also found in winter muscle and adipose tissue, respectively. The observed reduction in ECS tone may promote fatty acid mobilization from body fat stores, and favor carbohydrate metabolism in skeletal muscle of hibernating bears. Additionally, high circulating level of the endocannabinoid-like compound N-oleoylethanolamide (OEA) in winter could favor lipolysis and fatty acid oxidation in peripheral tissues. We also speculated on a role of OEA in the conservation of an anorexigenic signal and in the maintenance of torpor during hibernation, while sustaining the capacity of bears to sense stimuli from the environment

Identification of new levers to fight muscle atrophy: benefit of the hibernating brown bear model.

DoctoralMuscle wasting affects millions of people around the world, including the elderly, people with illnesses, and people who are immobilised for long periods of time. The loss of muscle mass leads to a decline in independence, promotes disease, increases resistance to treatment, and is associated with increased mortality. As a result, muscle wasting is a major public health problem. Many biomolecular mechanisms have been documented to explain the occurrence of muscle wasting, mainly through the use of laboratory rodent models. However, no treatment is really effective and/or adaptable for all today. The main objective of this thesis was to find new underlying mechanisms that could become therapeutic targets to combat muscle atrophy in humans. We chose an approach based on biomimicry. Our strategy was (1) to perform a comparative physiology study between the brown bear model naturally resistant to atrophy during hibernation and the unloading mouse sensitive to muscle atrophy, (2) to study the role of the ATF4 and TGF-β/BMP signalling pathways in these two models, and finally(3) to initiate studies on human muscle cells to validate the hypotheses from the first two studies. In our first study, the strategy was to identify genes differentially regulated in brown bear muscle between the hibernation and active periods. Then we compared them to those differentially regulated in the muscles of the unloading mouse versus the control mouse. We showed that the concomitance of inhibition of TGF-β signalling and induction of BMP signalling appeared to be crucial for the maintenance of muscle mass under conditions of prolonged physical inactivity. In our second study, we showed that the induction of the ATF4 signalling pathway in muscle was uncoupled from muscle atrophy in healthy and physically inactive mice when previously treated with the halofuginone molecule, and also in hibernating bears. In all three situations, the maintenance of muscle mass was associated with both the induction of ATF4 and BMP signalling and the inhibition of TGF-β. Finally, preliminary results obtained by cultivating human muscle cells with hibernating brown bear serum suggest the presence of a circulating active compound that may mimic some of the characteristics observed in atrophy-resistant hibernating brown bear muscle. In conclusion, this work providesnumerous perspectives in the modulation of the balance of TGF-β and BMP signalling pathways in situations of prolonged physical inactivity. In addition, it opens up new research on the identification of active compounds in bear serum that could be used in the human clinic to limit or prevent the onset of muscle atrophy during immobilisation or in other pathophysiological conditions

Identification de nouveaux leviers pour lutter contre l’atrophie musculaire : bénéfice du modèle de l’ours brun en hibernation

Muscle wasting affects millions of people around the world, including the elderly, people with illnesses, and people who are immobilised for long periods of time. The loss of muscle mass leads to a decline in independence, promotes disease, increases resistance to treatment, and is associated with increased mortality. As a result, muscle wasting is a major public health problem. Many biomolecular mechanisms have been documented to explain the occurrence of muscle wasting, mainly through the use of laboratory rodent models. However, no treatment is really effective and/or adaptable for all today. The main objective of this thesis was to find new underlying mechanisms that could become therapeutic targets to combat muscle atrophy in humans. We chose an approach based on biomimicry. Our strategy was (1) to perform a comparative physiology study between the brown bear model naturally resistant to atrophy during hibernation and the unloading mouse sensitive to muscle atrophy, (2) to study the role of the ATF4 and TGF-β/BMP signalling pathways in these two models, and finally (3) to initiate studies on human muscle cells to validate the hypotheses from the first two studies. In our first study, the strategy was to identify genes differentially regulated in brown bear muscle between the hibernation and active periods. Then we compared them to those differentially regulated in the muscles of the unloading mouse versus the control mouse. We showed that the concomitance of inhibition of TGF-β signalling and induction of BMP signalling appeared to be crucial for the maintenance of muscle mass under conditions of prolonged physical inactivity. In our second study, we showed that the induction of the ATF4 signalling pathway in muscle was uncoupled from muscle atrophy in healthy and physically inactive mice when previously treated with the halofuginone molecule, and also in hibernating bears. In all three situations, the maintenance of muscle mass was associated with both the induction of ATF4 and BMP signalling and the inhibition of TGF-β. Finally, preliminary results obtained by cultivating human muscle cells with hibernating brown bear serum suggest the presence of a circulating active compound that may mimic some of the characteristics observed in atrophy-resistant hibernating brown bear muscle. In conclusion, this work provides numerous perspectives in the modulation of the balance of TGF-β and BMP signalling pathways in situations of prolonged physical inactivity. In addition, it opens up new research on the identification of active compounds in bear serum that could be used in the human clinic to limit or prevent the onset of muscle atrophy during immobilisation or in other pathophysiological conditions.L'atrophie musculaire impacte des millions de personnes à travers le monde, inlcuant des personnes âgées, des personnes atteintes de maladies ou encore des personnes immobilisées pendant de longues périodes. La perte de masse musculaire conduit à un déclin de l'autonomie, favorise l'apparition de maladies, augmente la résistance aux traitements mis en place, et est associée à une augmentation de la mortalité. De ce fait, l'atrophie musculaire constitue un problème majeur de santé publique. Enormément de mécanismes biomoléculaires ont été documentés pouvant expliquer l'apparition de l'atrophie musculaire, principalement grâce à l'utilisation de modèle de rongeurs de laboratoire. Pourtant, aucun traitement n'est réellement efficace et/ou adaptable pour tous aujourd'hui. L'objectif principal de cette thèse était de trouver de nouveaux mécanismes sous-jacents qui pourraient devenir des cibles thérapeutiques pour combattre l'atrophie musculaire chez l'Homme. Nous avons choisi une approche basée sur le biomimétisme. Notre stratégie a été (1) de réaliser une étude de physiologie comparée entre le modèle de l’ours brun naturellement résistant à l'atrophie pendant hibernation et la souris suspendue sensible à l’atrophie musculaire, (2) d’étudier le rôle des voies de signalisations ATF4 et TGF-β/BMP dans ces deux modèles, et enfin (3) d’initier des études sur des cellules musculaires humaines pour valider les hypothèses issues des deux premières études. Dans notre première étude, la stratégie a été d’identifier les gènes différentiellement régulés dans les muscles de l'ours brun entre la période d’hibernation et la période d’activité. Ensuite, nous les avons comparés à ceux différentiellement régulés dans les muscles de la souris suspendue par rapport à la souris contrôle. Nous avons montré que la concomitance de l’inhibition de la signalisation TGF-b et de l’induction de la signalisation BMP semblait être cruciale pour le maintien de la masse musculaire en condition d'inactivité physique prolongée. Dans notre deuxième étude, nous avons montré que l’induction de la voie de signalisation d’ATF4 dans le muscle était découplée de l’atrophie musculaire chez la souris saine ou soumise à une situation d’inactivité physique lorsqu’elles étaient préalablement traitées par la molécule d’halofuginone, et également chez l’ours hibernant. Dans ces 3 situations, le maintien de la masse musculaire était associé à la fois à l’induction de la signalisation d’ATF4 et de BMP et à l’inhibition de TGF-β. Enfin, des résultats préliminaires obtenus en cultivant des cellules musculaires humaines avec du sérum d'ours brun hibernant suggèrent la présence d'un composé actif circulant pouvant reproduire certaines caractéristiques observées dans le muscle de l'ours brun hibernant résistant à l'atrophie. En conclusion, ces travaux ouvrent de nombreuses perspectives dans la modulation de la balance des voies de signalisation TGF-b et BMP dans des situations d'inactivité physique prolongée. De plus, ils ouvrent de nouvelles recherches sur l'identification de composés actifs dans le sérum de l'ours pouvant être utilisables en clinique humaine afin de limiter ou prévenir l'apparition d'atrophie musculaire lors de l’immobilisation ou dans d'autres conditions physiopathologiques

Identification de nouveaux leviers pour lutter contre l’atrophie musculaire : bénéfice du modèle de l’ours brun en hibernation

L'atrophie musculaire impacte des millions de personnes à travers le monde, inlcuant des personnes âgées, des personnes atteintes de maladies ou encore des personnes immobilisées pendant de longues périodes. La perte de masse musculaire conduit à un déclin de l'autonomie, favorise l'apparition de maladies, augmente la résistance aux traitements mis en place, et est associée à une augmentation de la mortalité. De ce fait, l'atrophie musculaire constitue un problème majeur de santé publique. Enormément de mécanismes biomoléculaires ont été documentés pouvant expliquer l'apparition de l'atrophie musculaire, principalement grâce à l'utilisation de modèle de rongeurs de laboratoire. Pourtant, aucun traitement n'est réellement efficace et/ou adaptable pour tous aujourd'hui. L'objectif principal de cette thèse était de trouver de nouveaux mécanismes sous-jacents qui pourraient devenir des cibles thérapeutiques pour combattre l'atrophie musculaire chez l'Homme. Nous avons choisi une approche basée sur le biomimétisme. Notre stratégie a été (1) de réaliser une étude de physiologie comparée entre le modèle de l’ours brun naturellement résistant à l'atrophie pendant hibernation et la souris suspendue sensible à l’atrophie musculaire, (2) d’étudier le rôle des voies de signalisations ATF4 et TGF-β/BMP dans ces deux modèles, et enfin (3) d’initier des études sur des cellules musculaires humaines pour valider les hypothèses issues des deux premières études. Dans notre première étude, la stratégie a été d’identifier les gènes différentiellement régulés dans les muscles de l'ours brun entre la période d’hibernation et la période d’activité. Ensuite, nous les avons comparés à ceux différentiellement régulés dans les muscles de la souris suspendue par rapport à la souris contrôle. Nous avons montré que la concomitance de l’inhibition de la signalisation TGF-b et de l’induction de la signalisation BMP semblait être cruciale pour le maintien de la masse musculaire en condition d'inactivité physique prolongée. Dans notre deuxième étude, nous avons montré que l’induction de la voie de signalisation d’ATF4 dans le muscle était découplée de l’atrophie musculaire chez la souris saine ou soumise à une situation d’inactivité physique lorsqu’elles étaient préalablement traitées par la molécule d’halofuginone, et également chez l’ours hibernant. Dans ces 3 situations, le maintien de la masse musculaire était associé à la fois à l’induction de la signalisation d’ATF4 et de BMP et à l’inhibition de TGF-β. Enfin, des résultats préliminaires obtenus en cultivant des cellules musculaires humaines avec du sérum d'ours brun hibernant suggèrent la présence d'un composé actif circulant pouvant reproduire certaines caractéristiques observées dans le muscle de l'ours brun hibernant résistant à l'atrophie. En conclusion, ces travaux ouvrent de nombreuses perspectives dans la modulation de la balance des voies de signalisation TGF-b et BMP dans des situations d'inactivité physique prolongée. De plus, ils ouvrent de nouvelles recherches sur l'identification de composés actifs dans le sérum de l'ours pouvant être utilisables en clinique humaine afin de limiter ou prévenir l'apparition d'atrophie musculaire lors de l’immobilisation ou dans d'autres conditions physiopathologiques.Muscle wasting affects millions of people around the world, including the elderly, people with illnesses, and people who are immobilised for long periods of time. The loss of muscle mass leads to a decline in independence, promotes disease, increases resistance to treatment, and is associated with increased mortality. As a result, muscle wasting is a major public health problem. Many biomolecular mechanisms have been documented to explain the occurrence of muscle wasting, mainly through the use of laboratory rodent models. However, no treatment is really effective and/or adaptable for all today. The main objective of this thesis was to find new underlying mechanisms that could become therapeutic targets to combat muscle atrophy in humans. We chose an approach based on biomimicry. Our strategy was (1) to perform a comparative physiology study between the brown bear model naturally resistant to atrophy during hibernation and the unloading mouse sensitive to muscle atrophy, (2) to study the role of the ATF4 and TGF-β/BMP signalling pathways in these two models, and finally (3) to initiate studies on human muscle cells to validate the hypotheses from the first two studies. In our first study, the strategy was to identify genes differentially regulated in brown bear muscle between the hibernation and active periods. Then we compared them to those differentially regulated in the muscles of the unloading mouse versus the control mouse. We showed that the concomitance of inhibition of TGF-β signalling and induction of BMP signalling appeared to be crucial for the maintenance of muscle mass under conditions of prolonged physical inactivity. In our second study, we showed that the induction of the ATF4 signalling pathway in muscle was uncoupled from muscle atrophy in healthy and physically inactive mice when previously treated with the halofuginone molecule, and also in hibernating bears. In all three situations, the maintenance of muscle mass was associated with both the induction of ATF4 and BMP signalling and the inhibition of TGF-β. Finally, preliminary results obtained by cultivating human muscle cells with hibernating brown bear serum suggest the presence of a circulating active compound that may mimic some of the characteristics observed in atrophy-resistant hibernating brown bear muscle. In conclusion, this work provides numerous perspectives in the modulation of the balance of TGF-β and BMP signalling pathways in situations of prolonged physical inactivity. In addition, it opens up new research on the identification of active compounds in bear serum that could be used in the human clinic to limit or prevent the onset of muscle atrophy during immobilisation or in other pathophysiological conditions

Identification de nouveaux leviers pour lutter contre l’atrophie musculaire : bénéfice du modèle de l’ours brun en hibernation

Muscle wasting affects millions of people around the world, including the elderly, people with illnesses, and people who are immobilised for long periods of time. The loss of muscle mass leads to a decline in independence, promotes disease, increases resistance to treatment, and is associated with increased mortality. As a result, muscle wasting is a major public health problem. Many biomolecular mechanisms have been documented to explain the occurrence of muscle wasting, mainly through the use of laboratory rodent models. However, no treatment is really effective and/or adaptable for all today. The main objective of this thesis was to find new underlying mechanisms that could become therapeutic targets to combat muscle atrophy in humans. We chose an approach based on biomimicry. Our strategy was (1) to perform a comparative physiology study between the brown bear model naturally resistant to atrophy during hibernation and the unloading mouse sensitive to muscle atrophy, (2) to study the role of the ATF4 and TGF-β/BMP signalling pathways in these two models, and finally (3) to initiate studies on human muscle cells to validate the hypotheses from the first two studies. In our first study, the strategy was to identify genes differentially regulated in brown bear muscle between the hibernation and active periods. Then we compared them to those differentially regulated in the muscles of the unloading mouse versus the control mouse. We showed that the concomitance of inhibition of TGF-β signalling and induction of BMP signalling appeared to be crucial for the maintenance of muscle mass under conditions of prolonged physical inactivity. In our second study, we showed that the induction of the ATF4 signalling pathway in muscle was uncoupled from muscle atrophy in healthy and physically inactive mice when previously treated with the halofuginone molecule, and also in hibernating bears. In all three situations, the maintenance of muscle mass was associated with both the induction of ATF4 and BMP signalling and the inhibition of TGF-β. Finally, preliminary results obtained by cultivating human muscle cells with hibernating brown bear serum suggest the presence of a circulating active compound that may mimic some of the characteristics observed in atrophy-resistant hibernating brown bear muscle. In conclusion, this work provides numerous perspectives in the modulation of the balance of TGF-β and BMP signalling pathways in situations of prolonged physical inactivity. In addition, it opens up new research on the identification of active compounds in bear serum that could be used in the human clinic to limit or prevent the onset of muscle atrophy during immobilisation or in other pathophysiological conditions.L'atrophie musculaire impacte des millions de personnes à travers le monde, inlcuant des personnes âgées, des personnes atteintes de maladies ou encore des personnes immobilisées pendant de longues périodes. La perte de masse musculaire conduit à un déclin de l'autonomie, favorise l'apparition de maladies, augmente la résistance aux traitements mis en place, et est associée à une augmentation de la mortalité. De ce fait, l'atrophie musculaire constitue un problème majeur de santé publique. Enormément de mécanismes biomoléculaires ont été documentés pouvant expliquer l'apparition de l'atrophie musculaire, principalement grâce à l'utilisation de modèle de rongeurs de laboratoire. Pourtant, aucun traitement n'est réellement efficace et/ou adaptable pour tous aujourd'hui. L'objectif principal de cette thèse était de trouver de nouveaux mécanismes sous-jacents qui pourraient devenir des cibles thérapeutiques pour combattre l'atrophie musculaire chez l'Homme. Nous avons choisi une approche basée sur le biomimétisme. Notre stratégie a été (1) de réaliser une étude de physiologie comparée entre le modèle de l’ours brun naturellement résistant à l'atrophie pendant hibernation et la souris suspendue sensible à l’atrophie musculaire, (2) d’étudier le rôle des voies de signalisations ATF4 et TGF-β/BMP dans ces deux modèles, et enfin (3) d’initier des études sur des cellules musculaires humaines pour valider les hypothèses issues des deux premières études. Dans notre première étude, la stratégie a été d’identifier les gènes différentiellement régulés dans les muscles de l'ours brun entre la période d’hibernation et la période d’activité. Ensuite, nous les avons comparés à ceux différentiellement régulés dans les muscles de la souris suspendue par rapport à la souris contrôle. Nous avons montré que la concomitance de l’inhibition de la signalisation TGF-b et de l’induction de la signalisation BMP semblait être cruciale pour le maintien de la masse musculaire en condition d'inactivité physique prolongée. Dans notre deuxième étude, nous avons montré que l’induction de la voie de signalisation d’ATF4 dans le muscle était découplée de l’atrophie musculaire chez la souris saine ou soumise à une situation d’inactivité physique lorsqu’elles étaient préalablement traitées par la molécule d’halofuginone, et également chez l’ours hibernant. Dans ces 3 situations, le maintien de la masse musculaire était associé à la fois à l’induction de la signalisation d’ATF4 et de BMP et à l’inhibition de TGF-β. Enfin, des résultats préliminaires obtenus en cultivant des cellules musculaires humaines avec du sérum d'ours brun hibernant suggèrent la présence d'un composé actif circulant pouvant reproduire certaines caractéristiques observées dans le muscle de l'ours brun hibernant résistant à l'atrophie. En conclusion, ces travaux ouvrent de nombreuses perspectives dans la modulation de la balance des voies de signalisation TGF-b et BMP dans des situations d'inactivité physique prolongée. De plus, ils ouvrent de nouvelles recherches sur l'identification de composés actifs dans le sérum de l'ours pouvant être utilisables en clinique humaine afin de limiter ou prévenir l'apparition d'atrophie musculaire lors de l’immobilisation ou dans d'autres conditions physiopathologiques

Get inspired by living : BMP/TGF balance for muscle atrophy resistance in hibernating bear muscle.

National audienc

Ubiquitin Ligases at the Heart of Skeletal Muscle Atrophy Control

International audienceSkeletal muscle loss is a detrimental side-effect of numerous chronic diseases that dramatically increases mortality and morbidity. The alteration of protein homeostasis is generally due to increased protein breakdown while, protein synthesis may also be down-regulated. The ubiquitin proteasome system (UPS) is a master regulator of skeletal muscle that impacts muscle contractile properties and metabolism through multiple levers like signaling pathways, contractile apparatus degradation, etc. Among the different actors of the UPS, the E3 ubiquitin ligases specifically target key proteins for either degradation or activity modulation, thus controlling both pro-anabolic or pro-catabolic factors. The atrogenes MuRF1/TRIM63 and MAFbx/Atrogin-1 encode for key E3 ligases that target contractile proteins and key actors of protein synthesis respectively. However, several other E3 ligases are involved upstream in the atrophy program, from signal transduction control to modulation of energy balance. Controlling E3 ligases activity is thus a tempting approach for preserving muscle mass. While indirect modulation of E3 ligases may prove beneficial in some situations of muscle atrophy, some drugs directly inhibiting their activity have started to appear. This review summarizes the main signaling pathways involved in muscle atrophy and the E3 ligases implicated, but also the molecules potentially usable for future therapies

Concurrent BMP maintenance and TGFβ inhibition is a hallmark of bear resistance to muscle atrophy

Muscle atrophy arises from a multiplicity of physiological or pathological situations (e.g., aging, physical inactivity, diabetes, cancers …) and its consequences are very detrimental at whole-body level. Even though knowledge of the underlying mechanisms keeps growing, there is still no proven treatment to date. To address this major clinical challenge, we selected here an innovative approach that compares muscle adaptations between an original model of natural resistance to muscle atrophy, the hibernating brown bear (Ursus arctos), and a classical model of physical inactivity-induced atrophy, the unloaded mouse. Throughout the hibernation season, the brown bear remains continuously torpid up for 5-7 months, without normothermic interbout arousals, and thus dealing with fasting and prolonged physical inactivity. Remarkably, even facing with these two main atrophic inducers, the bear has the unique ability to withstand muscle loss. Using transcriptomic analysis by RNA sequencing, we identified 2693 differentially expressed genes between the active versus hibernating period in bear muscle. A general downregulation of genes involved in extracellular matrix structure organization was observed in the hibernating brown bear. We then decided to focus on TGF-β superfamily including i) the TGF-β signaling being a master regulator of the extracellular matrix organization, and as well involved in muscle mass loss and ii) the BMP signaling, recently discovered involved in muscle mass maintenance. During hibernation, gene expression of the TGF-β and BMP pathways components was overall downregulated and upregulated, respectively. On the contrary, an increased expression of TGF-β signaling genes and a decreased expression of BMP signaling genes was observed in mice muscles during physical inactivity. We have further substantiated this opposite regulation between atrophied muscles of the unloaded mouse and non-atrophied muscles of the hibernating bear at the protein level. Altogether, our data identified a balance between TGF-β and BMP signaling pathways as crucial for muscle mass maintenance during long-term physical inactivity. In addition to the TGF-β pathway, already targeted in a wide range of therapies, the BMP pathway therefore appears to be an additional potential therapeutic target to prevent muscle atrophy

Concurrent BMP maintenance and TGFβ inhibition is a hallmark of bear resistance to muscle atrophy

Muscle atrophy arises from a multiplicity of physiological or pathological situations (e.g., aging, physical inactivity, diabetes, cancers …) and its consequences are very detrimental at whole-body level. Even though knowledge of the underlying mechanisms keeps growing, there is still no proven treatment to date. To address this major clinical challenge, we selected here an innovative approach that compares muscle adaptations between an original model of natural resistance to muscle atrophy, the hibernating brown bear (Ursus arctos), and a classical model of physical inactivity-induced atrophy, the unloaded mouse. Throughout the hibernation season, the brown bear remains continuously torpid up for 5-7 months, without normothermic interbout arousals, and thus dealing with fasting and prolonged physical inactivity. Remarkably, even facing with these two main atrophic inducers, the bear has the unique ability to withstand muscle loss. Using transcriptomic analysis by RNA sequencing, we identified 2693 differentially expressed genes between the active versus hibernating period in bear muscle. A general downregulation of genes involved in extracellular matrix structure organization was observed in the hibernating brown bear. We then decided to focus on TGF-β superfamily including i) the TGF-β signaling being a master regulator of the extracellular matrix organization, and as well involved in muscle mass loss and ii) the BMP signaling, recently discovered involved in muscle mass maintenance. During hibernation, gene expression of the TGF-β and BMP pathways components was overall downregulated and upregulated, respectively. On the contrary, an increased expression of TGF-β signaling genes and a decreased expression of BMP signaling genes was observed in mice muscles during physical inactivity. We have further substantiated this opposite regulation between atrophied muscles of the unloaded mouse and non-atrophied muscles of the hibernating bear at the protein level. Altogether, our data identified a balance between TGF-β and BMP signaling pathways as crucial for muscle mass maintenance during long-term physical inactivity. In addition to the TGF-β pathway, already targeted in a wide range of therapies, the BMP pathway therefore appears to be an additional potential therapeutic target to prevent muscle atrophy

Concurrent BMP signaling maintenance and TGF- β signaling inhibition is a hallmark of natural resistance to muscle atrophy

National audienceMuscle atrophy arises from a multiplicity of physiological or pathological situations (e.g. diabetes, cancers, aging, physical inactivity…) and its consequences are very detrimental at whole-body level. Even though knowledge of the underlying mechanisms keeps growing, there is still no proven treatment to date. To address this major clinical challenge, we selected here an innovative approach that compares muscle adaptations between an original model of natural resistance to muscle atrophy, the hibernating brown bear, and a classical model of disuse-induced atrophy in mouse. Remarkably, the bear has the unique ability to withstand muscle loss during hibernation, being able to cope with main triggers of atrophy, physical inactivity and prolonged fasting. Using transcriptomic analysis by RNA sequencing, we identified 2693 differentially expressed genes between the active versus hibernating period in bear muscle. We focused on TGF-β and BMP signaling pathways that are respectively involved in muscle mass loss and maintenance. During hibernation, gene expression of the TGF-β and BMP pathways components was overall downregulated and upregulated, respectively. On the contrary, an increased expression of TGF-β signaling genes and a decreased expression of BMP signaling genes was observed in mice muscles during unloading. We have further substantiated this opposite regulation between atrophied muscles of the unloaded mouse and non-atrophied muscles of the hibernating bear at the protein level. Altogether, our data identified a balance between TGF-β and BMP signaling pathways as crucial for muscle mass maintenance during long-term physical inactivity. In addition to the TGF-β pathway, already targeted in a wide range of therapies, the BMP pathway therefore appears to be an additional potential therapeutic target to prevent muscle atrophy