Growth & Development (Handschin)Head of Research Unit Prof. Dr.Christoph HandschinOverviewMembersPublicationsProjects & CollaborationsProjects & Collaborations OverviewMembersPublicationsProjects & Collaborations Projects & Collaborations 41 foundShow per page10 10 20 50 Investigating the Neuromuscular Involvement in Cachexia: Identifying Novel Target Genes and Therapeutic Targets Research Project | 2 Project MembersCancer cachexia is a severe and prevalent condition that affects up to 80% of cancer patients and causes muscle wasting and weakness, leading to frailty and reduced tolerance to cancer treatments. Despite its significant contribution to cancer-related morbidity and mortality, there are currently no effective treatment strategies to ameliorate cachexia. This highlights the need for further research to understand the mechanisms behind cachexia development. Recent studies indicate that changes in the connection between the nervous system and muscles, called the neuromuscular junction (NMJ), play a crucial role in developing cachexia. However, the specific mechanisms behind these alterations and how they mediate muscle wasting are not understood. The primary goal of this project is to use state-of-the-art techniques to investigate NMJs in both cachexia-susceptible and -protected muscles in mouse models of cachexia. Revealing the differences in different muscle types will provide novel information about the underlying causes of cachexia. Furthermore, we aim to genetically manipulate the factors revealed in this study to restore muscle wasting in mice with cancer. By this means, new potential therapeutic targets for treating cachexia will be identified. Ultimately, this research project aims to decipher the underlying neuromuscular causes of cancer cachexia and identify new treatment options that may enhance the quality of life and survival of cancer patients. Beitrag an die Fertigstellung der Dissertation "Transcriptional networks in skeletal muscle in response to acute exercise" Research Project | 2 Project MembersWestliche Gesellschaften leiden zunehmend unter Wohlstandskrankheiten die auf einen inaktiven Lebensstil und einen Überschuss an Kalorien zurückzuführen sind. Im Jahr 2020 gehörten Herz-Kreislauf-Erkrankungen, Diabetes und Demenz zu den häufigsten Todesursachen in der Schweiz; selbst während dem Höhepunkt der Covid19-Pandemie. Die Gemeinsamkeit all dieser Krankheiten ist die mögliche Prävention und Therapie durch körperliche Aktivität. Körperliche Fitness ist ein epidemiologischer Indikator für reduzierte Mortalität und Anfälligkeit für Krankheiten was regelmässiges Training zur absoluten Grundlage eines gesunden Lebensstils macht. Während wir aus physiologischer Sicht verstehen, wie sich die Muskulatur auf regelmässiges Training einstellt und dadurch die gesamte körperliche Gesundheit positiv beeinflusst, so sind die molekularen Prozesse die diese Veränderungen steuern weitgehend unbekannt. Das Ziel meines Doktorats ist es, genau diese molekularen Prozesse im Muskel besser zu verstehen und die wichtigsten Transkriptionsfaktoren in der Muskelanpassung zu identifizieren und charakterisieren. Structure-function analysis of the RNA-binding protein PGC-1a in skeletal muscle Research Project | 2 Project MembersPlasticity of cells, tissues and organs relies on sensing of external and internal cues, integration of the engaged signaling pathways, and orchestration of a pleiotropic response. For example, contractile patterns, ambient temperature and oxygen levels, nutrient availability and composition, as well as other factors result in a massive remodeling of biochemical pathways, cellular metabolism and mechanical properties of skeletal muscle cells, most notably in the context of repeated bouts of exercise, ultimately leading to training adaptations. In turn, such adaptations of skeletal muscle trigger internal and external changes that contribute to the systemic effects of exercise with many health benefits, and strong preventative and therapeutic outcomes in a number of pathologies. Surprisingly, even though the physiological and clinical contributions of exercise-linked muscle plasticity are well recognized, the molecular mechanisms that control the corresponding biological programs are still poorly understood. In recent years, the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) has emerged as a central regulatory nexus of plasticity in various cell types. PGC-1α integrates upstream signaling pathways to coordinate the complex transcriptional networks encoding biological programs involved in mitochondrial function, cellular metabolism and more. In the case of endurance exercise-mediated plasticity of muscle cells, most, if not all of the adaptations are evoked by this stimulus. Accordingly, muscle-specific overexpression or knockout of PGC-1α elicits high endurance and pathologically sedentary phenotypes, respectively. Our proposal aims at elucidating the molecular underpinnings of the complex transcriptional control that is exerted by PGC-1α in a spatio-temporal manner. We have recently discovered that the binding of RNAs to PGC-1α contributes to full transcriptional activity, and is central for the inclusion of PGC-1α-containing multiprotein complexes in liquid-liquid phase separated nuclear condensates for the sequestration of transcription. We now plan to determine the list and common features of PGC-1α-bound RNAs, interrogate how RNA binding is brought about in a structure-function analysis, study the consequences on multiprotein complex formation, and ultimately investigate the physiological relevance in skeletal muscle cells in vitro and in vivo . To do so, novel animal models will be leveraged for single-end enhanced crosslinking and immunoprecipitation (seCLIP) experiments to identify PGC-1α-bound RNAs, structural information will be obtained by NMR spectroscopy, and validated using site-directed mutagenesis of key amino acids and nucleotides in PGC-1α and RNAs, respectively, to study PGC-1α-dependent liquid-liquid phase separation. Then, PGC-1α-containing multiprotein complexes will be co-purified to perform cryo-electron microscopy-based single particle structural analysis. Finally, the functional consequence of targeted mutagenesis of key residues will be assessed in muscle cells in culture and mouse muscle in vivo with state-of-the-art myotropic adeno-associated viral vectors (AAVMYO). The research plan thus a.) highly synergizes in terms of interdisciplinary approaches between the groups involved and b.) will result in hitherto unprecedented insights into molecular mechanisms that underlie complex spatio-temporal control of transcriptional networks with important implications for the understanding of cellular and tissue plasticity in health and disease. Temporal trajectory of epigenetic and transcriptional regulation of the training response in skeletal muscle Research Project | 1 Project MembersNo Description available A novel role of dysferlin in regulating skeletal muscle metabolism contributes to disease pathology in dysferlinopathies Research Project | 1 Project MembersDysferlin is a protein that is intimately involved in the control of membrane repair in damaged cells. Accordingly, mutations of the dysferlin gene cause progressive muscular dystrophies collectively referred to as dysferlinopathies. Unexpectedly though, therapeutic strategies aimed at restoring membrane resealing capabilities fail to prevent the muscular dystrophy in these diseases, indicating other, hitherto unknown molecular functions of dysferlin to contribute to the pathology in dysferlinopathy patients. We have now observed how the pathological progression in a mouse model for Limb-Girdle Muscular Dystrophy type 2B (LGMD2B) is closely linked to altered muscle cell metabolism, most notably an accumulation of glycogen. Moreover, exacerbation of glycogen storage by overexpression of the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) in these muscles results in a more severe muscle tissue damage, and impaired functionality. Our preliminary data thus indicate that abnormal muscle cell metabolism caused by mutations in the dysferlin gene contribute to the disease pathology, that dysferlinopathies recapitulate some of the aberrant changes observed in glycogen storage diseases such as McArdle's, and finally that dysferlin regulates cellular metabolism in an unknown manner, in addition to its role in controlling membrane repair. We therefore propose a research plan in this grant application that aims at a.) substantiating and validating these findings in different pre-clinical models, b.) obtaining proof-of-concept for therapeutic efficacy of normalization of muscle cell metabolism in LGMD2B, and c.) investigating the molecular underpinnings of the involvement of dysferlin in the regulation of muscle cell metabolism. The expected results will not only shed light on novel aspects of dysferlin function, but should also propose new therapeutic avenues to ameliorate this muscular dystrophies, complementing those targeting membrane repair. Involvement of metabolic remodeling in the development of the dystrophic phenotype in dysferlinopathies Research Project | 1 Project MembersDysferlinopathies are muscular dystrophies that are caused by a mutation in the dysferlin gene. Dysferlin plays a prominent role in membrane repair and dysferlin-deficient muscles develop a progressive muscular dystrophy. Currently, effective treatments for dysferlinopathies are lacking. Unexpectedly, even though experimental approaches can successfully restore membrane repair, muscles remain dystrophic, suggesting that additional, so-far unknown dysferlin-dependent functions might be involved in the development of the pathological phenotype. Therefore, alternative or complementary therapeutic interventions are needed. In many muscle diseases including Duchenne muscular dystrophy, overexpression of PGC-1α (peroxisome proliferator‐activated receptor γ coactivator 1α) in skeletal muscle ameliorates muscle fiber atrophy, integrity and function. Therefore, we were interested in the therapeutic effect of muscle PGC-1α on dysferlinopathy. Surprisingly however, the pathology of dysferlin-deficient mice was exacerbated by elevated levels of PGC-1α. This accelerated disease progression unveiled novel aspects that could be crucial for the development of the dystrophy. Our experiments revealed an altered metabolic phenotype in dysferlin-deficient muscles, which might contribute to disease etiology and progression. To elucidate the implications of these observations, our project aims at further unraveling the involvement of this metabolic remodeling in the development of the dystrophic phenotype. A better understanding of the disease patho-etiology could open novel therapeutic avenues to treat this muscular dystrophy. Involvement of metabolic remodeling in the development of the dystrophic phenotype in dysferlinopathies Research Project | 1 Project MembersDysferlinopathies are muscular dystrophies that are caused by a mutation in the dysferlin gene. Dysferlin plays a prominent role in membrane repair and dysferlin-deficient muscles develop a progressive muscular dystrophy. Currently, effective treatments for dysferlinopathies are lacking. Unexpectedly, even though experimental approaches can successfully restore membrane repair, muscles remain dystrophic, suggesting that additional, so-far unknown dysferlin-dependent functions might be involved in the development of the pathological phenotype. Therefore, alternative or complementary therapeutic interventions are needed. In many muscle diseases including Duchenne muscular dystrophy, overexpression of PGC-1α (peroxisome proliferator‐activated receptor γ coactivator 1α) in skeletal muscle ameliorates muscle fiber atrophy, integrity and function. Therefore, we were interested in the potential therapeutic effect of muscle PGC-1α on dysferlinopathy. Surprisingly however, the pathology of dysferlin-deficient mice was exacerbated by elevated levels of PGC-1α. Our experiments furthermore revealed an altered metabolic phenotype in dysferlin-deficient muscles, which might contribute to disease etiology and progression. To elucidate the implications of these observations, our projects aims at further unraveling the involvement of this metabolic remodeling in the development of the dystrophic phenotype. A better understanding of the disease patho-etiology could open novel therapeutic avenues to treat this muscular dystrophy. Treatment of sarcopenia with pulsatile, low-dose application of the myokine interleukin 6 (IL-6) Research Project | 1 Project MembersNo Description available Involvement of the transcriptional coregulator PERIOD2 in the regulation of skeletal muscle mitochondrial function Research Project | 1 Project MembersInvolvement of the transcriptional coregulator PERIOD2 in the regulation of skeletal muscle mitochondrial function Molecular mechanisms controlling the crosstalk between skeletal muscle and neurons Research Project | 1 Project MembersSkeletal muscle exhibits an enormous cellular plasticity to adapt to external and internal stimuli. For example, exercise triggers a pleiotropic adaptation in metabolic and contractile properties in muscle fibers, angiogenesis and increased vascularization within muscle tissue, as well as systemic metabolic remodeling in various other organs. Even though exercise exerts numerous health benefits, the molecular mechanisms that control muscle cell plasticity are still poorly understood. In particular, it is largely unclear how long-term adaptations of training are controlled, e.g. those related to the remodeling of the neuromuscular junction. Our grant aims at elucidating the transcriptional networks that control muscle cell identity in acute exercise and chronic exercise training. Preliminary data indicate that epigenetic adaptations in trained muscle might facilitate the gene expression changes elicited by individual exercise bouts. Besides a general analysis of these networks using a combination of next generation sequencing approaches and computational predictions, we will also specifically focus on potential mediators of a crosstalk between muscle fibers and neurons. We have previously published a hitherto unexpected retrograde effect of muscle on morphological and functional aspects of the motor neuron, mediated by so-far unknown effectors. Moreover, preliminary findings describing a potent effect of exercise and muscle peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a regulatory nexus of endurance exercise adaptation, on motor coordination and balance, and hence presumably proprioceptive and/or vestibular input indicate an even more extensive retrograde signaling between muscle and neuronal circuits. We thus plan to study the interaction of the neuromuscular, proprioceptive and vestibular systems, and to identify the respective mediators in this crosstalk. Retro- and anterograde mapping of proprioceptive and vestibular input on specific motor neuron pools will allow a fine-grained quantification of changes in these systems. These studies will not only contribute to a better understanding of neuromuscular physiology, but also help to identify factors that modulate neuromuscular junction stability, motor coordination and balance, all of which are affected in different pathological settings, e.g. in sarcopenia and aging. 12345 1...5 OverviewMembersPublicationsProjects & Collaborations
Projects & Collaborations 41 foundShow per page10 10 20 50 Investigating the Neuromuscular Involvement in Cachexia: Identifying Novel Target Genes and Therapeutic Targets Research Project | 2 Project MembersCancer cachexia is a severe and prevalent condition that affects up to 80% of cancer patients and causes muscle wasting and weakness, leading to frailty and reduced tolerance to cancer treatments. Despite its significant contribution to cancer-related morbidity and mortality, there are currently no effective treatment strategies to ameliorate cachexia. This highlights the need for further research to understand the mechanisms behind cachexia development. Recent studies indicate that changes in the connection between the nervous system and muscles, called the neuromuscular junction (NMJ), play a crucial role in developing cachexia. However, the specific mechanisms behind these alterations and how they mediate muscle wasting are not understood. The primary goal of this project is to use state-of-the-art techniques to investigate NMJs in both cachexia-susceptible and -protected muscles in mouse models of cachexia. Revealing the differences in different muscle types will provide novel information about the underlying causes of cachexia. Furthermore, we aim to genetically manipulate the factors revealed in this study to restore muscle wasting in mice with cancer. By this means, new potential therapeutic targets for treating cachexia will be identified. Ultimately, this research project aims to decipher the underlying neuromuscular causes of cancer cachexia and identify new treatment options that may enhance the quality of life and survival of cancer patients. Beitrag an die Fertigstellung der Dissertation "Transcriptional networks in skeletal muscle in response to acute exercise" Research Project | 2 Project MembersWestliche Gesellschaften leiden zunehmend unter Wohlstandskrankheiten die auf einen inaktiven Lebensstil und einen Überschuss an Kalorien zurückzuführen sind. Im Jahr 2020 gehörten Herz-Kreislauf-Erkrankungen, Diabetes und Demenz zu den häufigsten Todesursachen in der Schweiz; selbst während dem Höhepunkt der Covid19-Pandemie. Die Gemeinsamkeit all dieser Krankheiten ist die mögliche Prävention und Therapie durch körperliche Aktivität. Körperliche Fitness ist ein epidemiologischer Indikator für reduzierte Mortalität und Anfälligkeit für Krankheiten was regelmässiges Training zur absoluten Grundlage eines gesunden Lebensstils macht. Während wir aus physiologischer Sicht verstehen, wie sich die Muskulatur auf regelmässiges Training einstellt und dadurch die gesamte körperliche Gesundheit positiv beeinflusst, so sind die molekularen Prozesse die diese Veränderungen steuern weitgehend unbekannt. Das Ziel meines Doktorats ist es, genau diese molekularen Prozesse im Muskel besser zu verstehen und die wichtigsten Transkriptionsfaktoren in der Muskelanpassung zu identifizieren und charakterisieren. Structure-function analysis of the RNA-binding protein PGC-1a in skeletal muscle Research Project | 2 Project MembersPlasticity of cells, tissues and organs relies on sensing of external and internal cues, integration of the engaged signaling pathways, and orchestration of a pleiotropic response. For example, contractile patterns, ambient temperature and oxygen levels, nutrient availability and composition, as well as other factors result in a massive remodeling of biochemical pathways, cellular metabolism and mechanical properties of skeletal muscle cells, most notably in the context of repeated bouts of exercise, ultimately leading to training adaptations. In turn, such adaptations of skeletal muscle trigger internal and external changes that contribute to the systemic effects of exercise with many health benefits, and strong preventative and therapeutic outcomes in a number of pathologies. Surprisingly, even though the physiological and clinical contributions of exercise-linked muscle plasticity are well recognized, the molecular mechanisms that control the corresponding biological programs are still poorly understood. In recent years, the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) has emerged as a central regulatory nexus of plasticity in various cell types. PGC-1α integrates upstream signaling pathways to coordinate the complex transcriptional networks encoding biological programs involved in mitochondrial function, cellular metabolism and more. In the case of endurance exercise-mediated plasticity of muscle cells, most, if not all of the adaptations are evoked by this stimulus. Accordingly, muscle-specific overexpression or knockout of PGC-1α elicits high endurance and pathologically sedentary phenotypes, respectively. Our proposal aims at elucidating the molecular underpinnings of the complex transcriptional control that is exerted by PGC-1α in a spatio-temporal manner. We have recently discovered that the binding of RNAs to PGC-1α contributes to full transcriptional activity, and is central for the inclusion of PGC-1α-containing multiprotein complexes in liquid-liquid phase separated nuclear condensates for the sequestration of transcription. We now plan to determine the list and common features of PGC-1α-bound RNAs, interrogate how RNA binding is brought about in a structure-function analysis, study the consequences on multiprotein complex formation, and ultimately investigate the physiological relevance in skeletal muscle cells in vitro and in vivo . To do so, novel animal models will be leveraged for single-end enhanced crosslinking and immunoprecipitation (seCLIP) experiments to identify PGC-1α-bound RNAs, structural information will be obtained by NMR spectroscopy, and validated using site-directed mutagenesis of key amino acids and nucleotides in PGC-1α and RNAs, respectively, to study PGC-1α-dependent liquid-liquid phase separation. Then, PGC-1α-containing multiprotein complexes will be co-purified to perform cryo-electron microscopy-based single particle structural analysis. Finally, the functional consequence of targeted mutagenesis of key residues will be assessed in muscle cells in culture and mouse muscle in vivo with state-of-the-art myotropic adeno-associated viral vectors (AAVMYO). The research plan thus a.) highly synergizes in terms of interdisciplinary approaches between the groups involved and b.) will result in hitherto unprecedented insights into molecular mechanisms that underlie complex spatio-temporal control of transcriptional networks with important implications for the understanding of cellular and tissue plasticity in health and disease. Temporal trajectory of epigenetic and transcriptional regulation of the training response in skeletal muscle Research Project | 1 Project MembersNo Description available A novel role of dysferlin in regulating skeletal muscle metabolism contributes to disease pathology in dysferlinopathies Research Project | 1 Project MembersDysferlin is a protein that is intimately involved in the control of membrane repair in damaged cells. Accordingly, mutations of the dysferlin gene cause progressive muscular dystrophies collectively referred to as dysferlinopathies. Unexpectedly though, therapeutic strategies aimed at restoring membrane resealing capabilities fail to prevent the muscular dystrophy in these diseases, indicating other, hitherto unknown molecular functions of dysferlin to contribute to the pathology in dysferlinopathy patients. We have now observed how the pathological progression in a mouse model for Limb-Girdle Muscular Dystrophy type 2B (LGMD2B) is closely linked to altered muscle cell metabolism, most notably an accumulation of glycogen. Moreover, exacerbation of glycogen storage by overexpression of the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) in these muscles results in a more severe muscle tissue damage, and impaired functionality. Our preliminary data thus indicate that abnormal muscle cell metabolism caused by mutations in the dysferlin gene contribute to the disease pathology, that dysferlinopathies recapitulate some of the aberrant changes observed in glycogen storage diseases such as McArdle's, and finally that dysferlin regulates cellular metabolism in an unknown manner, in addition to its role in controlling membrane repair. We therefore propose a research plan in this grant application that aims at a.) substantiating and validating these findings in different pre-clinical models, b.) obtaining proof-of-concept for therapeutic efficacy of normalization of muscle cell metabolism in LGMD2B, and c.) investigating the molecular underpinnings of the involvement of dysferlin in the regulation of muscle cell metabolism. The expected results will not only shed light on novel aspects of dysferlin function, but should also propose new therapeutic avenues to ameliorate this muscular dystrophies, complementing those targeting membrane repair. Involvement of metabolic remodeling in the development of the dystrophic phenotype in dysferlinopathies Research Project | 1 Project MembersDysferlinopathies are muscular dystrophies that are caused by a mutation in the dysferlin gene. Dysferlin plays a prominent role in membrane repair and dysferlin-deficient muscles develop a progressive muscular dystrophy. Currently, effective treatments for dysferlinopathies are lacking. Unexpectedly, even though experimental approaches can successfully restore membrane repair, muscles remain dystrophic, suggesting that additional, so-far unknown dysferlin-dependent functions might be involved in the development of the pathological phenotype. Therefore, alternative or complementary therapeutic interventions are needed. In many muscle diseases including Duchenne muscular dystrophy, overexpression of PGC-1α (peroxisome proliferator‐activated receptor γ coactivator 1α) in skeletal muscle ameliorates muscle fiber atrophy, integrity and function. Therefore, we were interested in the therapeutic effect of muscle PGC-1α on dysferlinopathy. Surprisingly however, the pathology of dysferlin-deficient mice was exacerbated by elevated levels of PGC-1α. This accelerated disease progression unveiled novel aspects that could be crucial for the development of the dystrophy. Our experiments revealed an altered metabolic phenotype in dysferlin-deficient muscles, which might contribute to disease etiology and progression. To elucidate the implications of these observations, our project aims at further unraveling the involvement of this metabolic remodeling in the development of the dystrophic phenotype. A better understanding of the disease patho-etiology could open novel therapeutic avenues to treat this muscular dystrophy. Involvement of metabolic remodeling in the development of the dystrophic phenotype in dysferlinopathies Research Project | 1 Project MembersDysferlinopathies are muscular dystrophies that are caused by a mutation in the dysferlin gene. Dysferlin plays a prominent role in membrane repair and dysferlin-deficient muscles develop a progressive muscular dystrophy. Currently, effective treatments for dysferlinopathies are lacking. Unexpectedly, even though experimental approaches can successfully restore membrane repair, muscles remain dystrophic, suggesting that additional, so-far unknown dysferlin-dependent functions might be involved in the development of the pathological phenotype. Therefore, alternative or complementary therapeutic interventions are needed. In many muscle diseases including Duchenne muscular dystrophy, overexpression of PGC-1α (peroxisome proliferator‐activated receptor γ coactivator 1α) in skeletal muscle ameliorates muscle fiber atrophy, integrity and function. Therefore, we were interested in the potential therapeutic effect of muscle PGC-1α on dysferlinopathy. Surprisingly however, the pathology of dysferlin-deficient mice was exacerbated by elevated levels of PGC-1α. Our experiments furthermore revealed an altered metabolic phenotype in dysferlin-deficient muscles, which might contribute to disease etiology and progression. To elucidate the implications of these observations, our projects aims at further unraveling the involvement of this metabolic remodeling in the development of the dystrophic phenotype. A better understanding of the disease patho-etiology could open novel therapeutic avenues to treat this muscular dystrophy. Treatment of sarcopenia with pulsatile, low-dose application of the myokine interleukin 6 (IL-6) Research Project | 1 Project MembersNo Description available Involvement of the transcriptional coregulator PERIOD2 in the regulation of skeletal muscle mitochondrial function Research Project | 1 Project MembersInvolvement of the transcriptional coregulator PERIOD2 in the regulation of skeletal muscle mitochondrial function Molecular mechanisms controlling the crosstalk between skeletal muscle and neurons Research Project | 1 Project MembersSkeletal muscle exhibits an enormous cellular plasticity to adapt to external and internal stimuli. For example, exercise triggers a pleiotropic adaptation in metabolic and contractile properties in muscle fibers, angiogenesis and increased vascularization within muscle tissue, as well as systemic metabolic remodeling in various other organs. Even though exercise exerts numerous health benefits, the molecular mechanisms that control muscle cell plasticity are still poorly understood. In particular, it is largely unclear how long-term adaptations of training are controlled, e.g. those related to the remodeling of the neuromuscular junction. Our grant aims at elucidating the transcriptional networks that control muscle cell identity in acute exercise and chronic exercise training. Preliminary data indicate that epigenetic adaptations in trained muscle might facilitate the gene expression changes elicited by individual exercise bouts. Besides a general analysis of these networks using a combination of next generation sequencing approaches and computational predictions, we will also specifically focus on potential mediators of a crosstalk between muscle fibers and neurons. We have previously published a hitherto unexpected retrograde effect of muscle on morphological and functional aspects of the motor neuron, mediated by so-far unknown effectors. Moreover, preliminary findings describing a potent effect of exercise and muscle peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a regulatory nexus of endurance exercise adaptation, on motor coordination and balance, and hence presumably proprioceptive and/or vestibular input indicate an even more extensive retrograde signaling between muscle and neuronal circuits. We thus plan to study the interaction of the neuromuscular, proprioceptive and vestibular systems, and to identify the respective mediators in this crosstalk. Retro- and anterograde mapping of proprioceptive and vestibular input on specific motor neuron pools will allow a fine-grained quantification of changes in these systems. These studies will not only contribute to a better understanding of neuromuscular physiology, but also help to identify factors that modulate neuromuscular junction stability, motor coordination and balance, all of which are affected in different pathological settings, e.g. in sarcopenia and aging. 12345 1...5
Investigating the Neuromuscular Involvement in Cachexia: Identifying Novel Target Genes and Therapeutic Targets Research Project | 2 Project MembersCancer cachexia is a severe and prevalent condition that affects up to 80% of cancer patients and causes muscle wasting and weakness, leading to frailty and reduced tolerance to cancer treatments. Despite its significant contribution to cancer-related morbidity and mortality, there are currently no effective treatment strategies to ameliorate cachexia. This highlights the need for further research to understand the mechanisms behind cachexia development. Recent studies indicate that changes in the connection between the nervous system and muscles, called the neuromuscular junction (NMJ), play a crucial role in developing cachexia. However, the specific mechanisms behind these alterations and how they mediate muscle wasting are not understood. The primary goal of this project is to use state-of-the-art techniques to investigate NMJs in both cachexia-susceptible and -protected muscles in mouse models of cachexia. Revealing the differences in different muscle types will provide novel information about the underlying causes of cachexia. Furthermore, we aim to genetically manipulate the factors revealed in this study to restore muscle wasting in mice with cancer. By this means, new potential therapeutic targets for treating cachexia will be identified. Ultimately, this research project aims to decipher the underlying neuromuscular causes of cancer cachexia and identify new treatment options that may enhance the quality of life and survival of cancer patients.
Beitrag an die Fertigstellung der Dissertation "Transcriptional networks in skeletal muscle in response to acute exercise" Research Project | 2 Project MembersWestliche Gesellschaften leiden zunehmend unter Wohlstandskrankheiten die auf einen inaktiven Lebensstil und einen Überschuss an Kalorien zurückzuführen sind. Im Jahr 2020 gehörten Herz-Kreislauf-Erkrankungen, Diabetes und Demenz zu den häufigsten Todesursachen in der Schweiz; selbst während dem Höhepunkt der Covid19-Pandemie. Die Gemeinsamkeit all dieser Krankheiten ist die mögliche Prävention und Therapie durch körperliche Aktivität. Körperliche Fitness ist ein epidemiologischer Indikator für reduzierte Mortalität und Anfälligkeit für Krankheiten was regelmässiges Training zur absoluten Grundlage eines gesunden Lebensstils macht. Während wir aus physiologischer Sicht verstehen, wie sich die Muskulatur auf regelmässiges Training einstellt und dadurch die gesamte körperliche Gesundheit positiv beeinflusst, so sind die molekularen Prozesse die diese Veränderungen steuern weitgehend unbekannt. Das Ziel meines Doktorats ist es, genau diese molekularen Prozesse im Muskel besser zu verstehen und die wichtigsten Transkriptionsfaktoren in der Muskelanpassung zu identifizieren und charakterisieren.
Structure-function analysis of the RNA-binding protein PGC-1a in skeletal muscle Research Project | 2 Project MembersPlasticity of cells, tissues and organs relies on sensing of external and internal cues, integration of the engaged signaling pathways, and orchestration of a pleiotropic response. For example, contractile patterns, ambient temperature and oxygen levels, nutrient availability and composition, as well as other factors result in a massive remodeling of biochemical pathways, cellular metabolism and mechanical properties of skeletal muscle cells, most notably in the context of repeated bouts of exercise, ultimately leading to training adaptations. In turn, such adaptations of skeletal muscle trigger internal and external changes that contribute to the systemic effects of exercise with many health benefits, and strong preventative and therapeutic outcomes in a number of pathologies. Surprisingly, even though the physiological and clinical contributions of exercise-linked muscle plasticity are well recognized, the molecular mechanisms that control the corresponding biological programs are still poorly understood. In recent years, the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) has emerged as a central regulatory nexus of plasticity in various cell types. PGC-1α integrates upstream signaling pathways to coordinate the complex transcriptional networks encoding biological programs involved in mitochondrial function, cellular metabolism and more. In the case of endurance exercise-mediated plasticity of muscle cells, most, if not all of the adaptations are evoked by this stimulus. Accordingly, muscle-specific overexpression or knockout of PGC-1α elicits high endurance and pathologically sedentary phenotypes, respectively. Our proposal aims at elucidating the molecular underpinnings of the complex transcriptional control that is exerted by PGC-1α in a spatio-temporal manner. We have recently discovered that the binding of RNAs to PGC-1α contributes to full transcriptional activity, and is central for the inclusion of PGC-1α-containing multiprotein complexes in liquid-liquid phase separated nuclear condensates for the sequestration of transcription. We now plan to determine the list and common features of PGC-1α-bound RNAs, interrogate how RNA binding is brought about in a structure-function analysis, study the consequences on multiprotein complex formation, and ultimately investigate the physiological relevance in skeletal muscle cells in vitro and in vivo . To do so, novel animal models will be leveraged for single-end enhanced crosslinking and immunoprecipitation (seCLIP) experiments to identify PGC-1α-bound RNAs, structural information will be obtained by NMR spectroscopy, and validated using site-directed mutagenesis of key amino acids and nucleotides in PGC-1α and RNAs, respectively, to study PGC-1α-dependent liquid-liquid phase separation. Then, PGC-1α-containing multiprotein complexes will be co-purified to perform cryo-electron microscopy-based single particle structural analysis. Finally, the functional consequence of targeted mutagenesis of key residues will be assessed in muscle cells in culture and mouse muscle in vivo with state-of-the-art myotropic adeno-associated viral vectors (AAVMYO). The research plan thus a.) highly synergizes in terms of interdisciplinary approaches between the groups involved and b.) will result in hitherto unprecedented insights into molecular mechanisms that underlie complex spatio-temporal control of transcriptional networks with important implications for the understanding of cellular and tissue plasticity in health and disease.
Temporal trajectory of epigenetic and transcriptional regulation of the training response in skeletal muscle Research Project | 1 Project MembersNo Description available
A novel role of dysferlin in regulating skeletal muscle metabolism contributes to disease pathology in dysferlinopathies Research Project | 1 Project MembersDysferlin is a protein that is intimately involved in the control of membrane repair in damaged cells. Accordingly, mutations of the dysferlin gene cause progressive muscular dystrophies collectively referred to as dysferlinopathies. Unexpectedly though, therapeutic strategies aimed at restoring membrane resealing capabilities fail to prevent the muscular dystrophy in these diseases, indicating other, hitherto unknown molecular functions of dysferlin to contribute to the pathology in dysferlinopathy patients. We have now observed how the pathological progression in a mouse model for Limb-Girdle Muscular Dystrophy type 2B (LGMD2B) is closely linked to altered muscle cell metabolism, most notably an accumulation of glycogen. Moreover, exacerbation of glycogen storage by overexpression of the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) in these muscles results in a more severe muscle tissue damage, and impaired functionality. Our preliminary data thus indicate that abnormal muscle cell metabolism caused by mutations in the dysferlin gene contribute to the disease pathology, that dysferlinopathies recapitulate some of the aberrant changes observed in glycogen storage diseases such as McArdle's, and finally that dysferlin regulates cellular metabolism in an unknown manner, in addition to its role in controlling membrane repair. We therefore propose a research plan in this grant application that aims at a.) substantiating and validating these findings in different pre-clinical models, b.) obtaining proof-of-concept for therapeutic efficacy of normalization of muscle cell metabolism in LGMD2B, and c.) investigating the molecular underpinnings of the involvement of dysferlin in the regulation of muscle cell metabolism. The expected results will not only shed light on novel aspects of dysferlin function, but should also propose new therapeutic avenues to ameliorate this muscular dystrophies, complementing those targeting membrane repair.
Involvement of metabolic remodeling in the development of the dystrophic phenotype in dysferlinopathies Research Project | 1 Project MembersDysferlinopathies are muscular dystrophies that are caused by a mutation in the dysferlin gene. Dysferlin plays a prominent role in membrane repair and dysferlin-deficient muscles develop a progressive muscular dystrophy. Currently, effective treatments for dysferlinopathies are lacking. Unexpectedly, even though experimental approaches can successfully restore membrane repair, muscles remain dystrophic, suggesting that additional, so-far unknown dysferlin-dependent functions might be involved in the development of the pathological phenotype. Therefore, alternative or complementary therapeutic interventions are needed. In many muscle diseases including Duchenne muscular dystrophy, overexpression of PGC-1α (peroxisome proliferator‐activated receptor γ coactivator 1α) in skeletal muscle ameliorates muscle fiber atrophy, integrity and function. Therefore, we were interested in the therapeutic effect of muscle PGC-1α on dysferlinopathy. Surprisingly however, the pathology of dysferlin-deficient mice was exacerbated by elevated levels of PGC-1α. This accelerated disease progression unveiled novel aspects that could be crucial for the development of the dystrophy. Our experiments revealed an altered metabolic phenotype in dysferlin-deficient muscles, which might contribute to disease etiology and progression. To elucidate the implications of these observations, our project aims at further unraveling the involvement of this metabolic remodeling in the development of the dystrophic phenotype. A better understanding of the disease patho-etiology could open novel therapeutic avenues to treat this muscular dystrophy.
Involvement of metabolic remodeling in the development of the dystrophic phenotype in dysferlinopathies Research Project | 1 Project MembersDysferlinopathies are muscular dystrophies that are caused by a mutation in the dysferlin gene. Dysferlin plays a prominent role in membrane repair and dysferlin-deficient muscles develop a progressive muscular dystrophy. Currently, effective treatments for dysferlinopathies are lacking. Unexpectedly, even though experimental approaches can successfully restore membrane repair, muscles remain dystrophic, suggesting that additional, so-far unknown dysferlin-dependent functions might be involved in the development of the pathological phenotype. Therefore, alternative or complementary therapeutic interventions are needed. In many muscle diseases including Duchenne muscular dystrophy, overexpression of PGC-1α (peroxisome proliferator‐activated receptor γ coactivator 1α) in skeletal muscle ameliorates muscle fiber atrophy, integrity and function. Therefore, we were interested in the potential therapeutic effect of muscle PGC-1α on dysferlinopathy. Surprisingly however, the pathology of dysferlin-deficient mice was exacerbated by elevated levels of PGC-1α. Our experiments furthermore revealed an altered metabolic phenotype in dysferlin-deficient muscles, which might contribute to disease etiology and progression. To elucidate the implications of these observations, our projects aims at further unraveling the involvement of this metabolic remodeling in the development of the dystrophic phenotype. A better understanding of the disease patho-etiology could open novel therapeutic avenues to treat this muscular dystrophy.
Treatment of sarcopenia with pulsatile, low-dose application of the myokine interleukin 6 (IL-6) Research Project | 1 Project MembersNo Description available
Involvement of the transcriptional coregulator PERIOD2 in the regulation of skeletal muscle mitochondrial function Research Project | 1 Project MembersInvolvement of the transcriptional coregulator PERIOD2 in the regulation of skeletal muscle mitochondrial function
Molecular mechanisms controlling the crosstalk between skeletal muscle and neurons Research Project | 1 Project MembersSkeletal muscle exhibits an enormous cellular plasticity to adapt to external and internal stimuli. For example, exercise triggers a pleiotropic adaptation in metabolic and contractile properties in muscle fibers, angiogenesis and increased vascularization within muscle tissue, as well as systemic metabolic remodeling in various other organs. Even though exercise exerts numerous health benefits, the molecular mechanisms that control muscle cell plasticity are still poorly understood. In particular, it is largely unclear how long-term adaptations of training are controlled, e.g. those related to the remodeling of the neuromuscular junction. Our grant aims at elucidating the transcriptional networks that control muscle cell identity in acute exercise and chronic exercise training. Preliminary data indicate that epigenetic adaptations in trained muscle might facilitate the gene expression changes elicited by individual exercise bouts. Besides a general analysis of these networks using a combination of next generation sequencing approaches and computational predictions, we will also specifically focus on potential mediators of a crosstalk between muscle fibers and neurons. We have previously published a hitherto unexpected retrograde effect of muscle on morphological and functional aspects of the motor neuron, mediated by so-far unknown effectors. Moreover, preliminary findings describing a potent effect of exercise and muscle peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a regulatory nexus of endurance exercise adaptation, on motor coordination and balance, and hence presumably proprioceptive and/or vestibular input indicate an even more extensive retrograde signaling between muscle and neuronal circuits. We thus plan to study the interaction of the neuromuscular, proprioceptive and vestibular systems, and to identify the respective mediators in this crosstalk. Retro- and anterograde mapping of proprioceptive and vestibular input on specific motor neuron pools will allow a fine-grained quantification of changes in these systems. These studies will not only contribute to a better understanding of neuromuscular physiology, but also help to identify factors that modulate neuromuscular junction stability, motor coordination and balance, all of which are affected in different pathological settings, e.g. in sarcopenia and aging.
