14 results on '"Katharina E. Meijboom"'
Search Results
2. Dysregulation of Tweak and Fn14 in skeletal muscle of spinal muscular atrophy mice
- Author
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Katharina E. Meijboom, Emma R. Sutton, Eve McCallion, Emily McFall, Daniel Anthony, Benjamin Edwards, Sabrina Kubinski, Ines Tapken, Ines Bünermann, Gareth Hazell, Nina Ahlskog, Peter Claus, Kay E. Davies, Rashmi Kothary, Matthew J. A. Wood, and Melissa Bowerman
- Subjects
Spinal muscular atrophy ,Survival motor neuron ,Smn ,Tweak ,Fn14 ,Glucose metabolism ,Diseases of the musculoskeletal system ,RC925-935 - Abstract
Abstract Background Spinal muscular atrophy (SMA) is a childhood neuromuscular disorder caused by depletion of the survival motor neuron (SMN) protein. SMA is characterized by the selective death of spinal cord motor neurons, leading to progressive muscle wasting. Loss of skeletal muscle in SMA is a combination of denervation-induced muscle atrophy and intrinsic muscle pathologies. Elucidation of the pathways involved is essential to identify the key molecules that contribute to and sustain muscle pathology. The tumor necrosis factor-like weak inducer of apoptosis (TWEAK)/TNF receptor superfamily member fibroblast growth factor-inducible 14 (Fn14) pathway has been shown to play a critical role in the regulation of denervation-induced muscle atrophy as well as muscle proliferation, differentiation, and metabolism in adults. However, it is not clear whether this pathway would be important in highly dynamic and developing muscle. Methods We thus investigated the potential role of the TWEAK/Fn14 pathway in SMA muscle pathology, using the severe Taiwanese Smn −/−; SMN2 and the less severe Smn 2B/− SMA mice, which undergo a progressive neuromuscular decline in the first three post-natal weeks. We also used experimental models of denervation and muscle injury in pre-weaned wild-type (WT) animals and siRNA-mediated knockdown in C2C12 muscle cells to conduct additional mechanistic investigations. Results Here, we report significantly dysregulated expression of Tweak, Fn14, and previously proposed downstream effectors during disease progression in skeletal muscle of the two SMA mouse models. In addition, siRNA-mediated Smn knockdown in C2C12 myoblasts suggests a genetic interaction between Smn and the TWEAK/Fn14 pathway. Further analyses of SMA, Tweak −/− , and Fn14 −/− mice revealed dysregulated myopathy, myogenesis, and glucose metabolism pathways as a common skeletal muscle feature, providing further evidence in support of a relationship between the TWEAK/Fn14 pathway and Smn. Finally, administration of the TWEAK/Fn14 agonist Fc-TWEAK improved disease phenotypes in the two SMA mouse models. Conclusions Our study provides mechanistic insights into potential molecular players that contribute to muscle pathology in SMA and into likely differential responses of the TWEAK/Fn14 pathway in developing muscle.
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- 2022
- Full Text
- View/download PDF
3. Combining multiomics and drug perturbation profiles to identify muscle-specific treatments for spinal muscular atrophy
- Author
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Katharina E. Meijboom, Viola Volpato, Jimena Monzón-Sandoval, Joseph M. Hoolachan, Suzan M. Hammond, Frank Abendroth, Olivier G. de Jong, Gareth Hazell, Nina Ahlskog, Matthew J.A. Wood, Caleb Webber, and Melissa Bowerman
- Subjects
Muscle biology ,Neuroscience ,Medicine - Abstract
Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by loss of survival motor neuron (SMN) protein. While SMN restoration therapies are beneficial, they are not a cure. We aimed to identify potentially novel treatments to alleviate muscle pathology combining transcriptomics, proteomics, and perturbational data sets. This revealed potential drug candidates for repurposing in SMA. One of the candidates, harmine, was further investigated in cell and animal models, improving multiple disease phenotypes, including lifespan, weight, and key molecular networks in skeletal muscle. Our work highlights the potential of multiple and parallel data-driven approaches for the development of potentially novel treatments for use in combination with SMN restoration therapies.
- Published
- 2021
- Full Text
- View/download PDF
4. Interventions Targeting Glucocorticoid-Krüppel-like Factor 15-Branched-Chain Amino Acid Signaling Improve Disease Phenotypes in Spinal Muscular Atrophy Mice
- Author
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Lisa M. Walter, Marc-Olivier Deguise, Katharina E. Meijboom, Corinne A. Betts, Nina Ahlskog, Tirsa L.E. van Westering, Gareth Hazell, Emily McFall, Anna Kordala, Suzan M. Hammond, Frank Abendroth, Lyndsay M. Murray, Hannah K. Shorrock, Domenick A. Prosdocimo, Saptarsi M. Haldar, Mukesh K. Jain, Thomas H. Gillingwater, Peter Claus, Rashmi Kothary, Matthew J.A. Wood, and Melissa Bowerman
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Medicine ,Medicine (General) ,R5-920 - Abstract
The circadian glucocorticoid-Krüppel-like factor 15-branched-chain amino acid (GC-KLF15-BCAA) signaling pathway is a key regulatory axis in muscle, whose imbalance has wide-reaching effects on metabolic homeostasis. Spinal muscular atrophy (SMA) is a neuromuscular disorder also characterized by intrinsic muscle pathologies, metabolic abnormalities and disrupted sleep patterns, which can influence or be influenced by circadian regulatory networks that control behavioral and metabolic rhythms. We therefore set out to investigate the contribution of the GC-KLF15-BCAA pathway in SMA pathophysiology of Taiwanese Smn−/−;SMN2 and Smn2B/− mouse models. We thus uncover substantial dysregulation of GC-KLF15-BCAA diurnal rhythmicity in serum, skeletal muscle and metabolic tissues of SMA mice. Importantly, modulating the components of the GC-KLF15-BCAA pathway via pharmacological (prednisolone), genetic (muscle-specific Klf15 overexpression) and dietary (BCAA supplementation) interventions significantly improves disease phenotypes in SMA mice. Our study highlights the GC-KLF15-BCAA pathway as a contributor to SMA pathogenesis and provides several treatment avenues to alleviate peripheral manifestations of the disease. The therapeutic potential of targeting metabolic perturbations by diet and commercially available drugs could have a broader implementation across other neuromuscular and metabolic disorders characterized by altered GC-KLF15-BCAA signaling. Keywords: Spinal muscular atrophy, KLF15, Glucocorticoids, Branched-chain amino acids, Metabolism, Therapy
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- 2018
- Full Text
- View/download PDF
5. Approaches to Gene Modulation Therapy for ALS
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Katharina E. Meijboom and Robert H. Brown
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Pharmacology ,MicroRNAs ,Superoxide Dismutase-1 ,C9orf72 Protein ,Amyotrophic Lateral Sclerosis ,Humans ,Pharmacology (medical) ,Neurology (clinical) ,Review ,Oligonucleotides, Antisense - Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease for which there is currently no robust therapy. Recent progress in understanding ALS disease mechanisms and genetics in combination with innovations in gene modulation strategies creates promising new options for the development of ALS therapies. In recent years, six gene modulation therapies have been tested in ALS patients. These target gain-of-function pathology of the most common ALS genes, SOD1, C9ORF72, FUS, and ATXN2, using adeno-associated virus (AAV)-mediated microRNAs and antisense oligonucleotides (ASOs). Here, we review the latest clinical and preclinical advances in gene modulation approaches for ALS, including gene silencing, gene correction, and gene augmentation. These techniques have the potential to positively impact the direction of future research trials and transform ALS treatments for this grave disease. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-022-01285-w.
- Published
- 2022
6. Dysregulation of the Tweak/Fn14 pathway in skeletal muscle of spinal muscular atrophy mice
- Author
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Melissa Bowerman, Kay E. Davies, Emily McFall, Benjamin Edwards, Rashmi Kothary, Daniel C. Anthony, Nina Ahlskog, Matthew J.A. Wood, Sabrina Kubinski, Katharina E. Meijboom, G Hazell, and Peter Claus
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business.industry ,Myogenesis ,Skeletal muscle ,Spinal muscular atrophy ,Motor neuron ,medicine.disease ,SMA ,Muscle atrophy ,medicine.anatomical_structure ,medicine ,Cancer research ,Myocyte ,medicine.symptom ,business ,Myopathy - Abstract
Spinal muscular atrophy (SMA) is a childhood neuromuscular disorder caused by depletion of the survival motor neuron (SMN) protein. SMA is characterized by the selective death of spinal cord motor neurons, leading to progressive muscle wasting. Loss of skeletal muscle in SMA is a combination of denervation-induced muscle atrophy and intrinsic muscle pathologies. Elucidation of the pathways involved is essential to identify the key molecules that contribute to and sustain muscle pathology. The tumor necrosis factor-like weak inducer of apoptosis (TWEAK)/TNF receptor superfamily member fibroblast growth factor inducible 14 (Fn14) pathway has been shown to play a critical role in the regulation of denervation-induced muscle atrophy as well as muscle proliferation, differentiation and metabolism in adults. However, it is not clear whether this pathway would be important in highly dynamic and developing muscle. We thus investigated the potential role of the TWEAK/Fn14 pathway in SMA muscle pathology, using the severe Taiwanese Smn-/-;SMN2 and the less severe Smn2B/- SMA mice, which undergo a progressive neuromuscular decline in the first three post-natal weeks. Here, we report significantly dysregulated expression of the TWEAK/Fn14 pathway during disease progression in skeletal muscle of the two SMA mouse models. In addition, siRNA-mediated Smn knockdown in C2C12 myoblasts suggests a genetic interaction between Smn and the TWEAK/Fn14 pathway. Further analyses of SMA, Tweak-/- and Fn14-/- mice revealed dysregulated myopathy, myogenesis and glucose metabolism pathways as a common skeletal muscle feature, and providing further evidence in support of a relationship between the TWEAK/Fn14 pathway and Smn. Finally, a pharmacological intervention (Fc-TWEAK) to upregulate the activity of the TWEAK/Fn14 pathway improved disease phenotypes in the two SMA mouse models. Our study provides novel mechanistic insights into the molecular players that contribute to muscle pathology in SMA and into the role of the TWEAK/Fn14 pathway in developing muscle.
- Published
- 2021
7. Dystrophin involvement in peripheral circadian SRF signalling
- Author
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Wooi F. Lim, Melissa Bowerman, Corinne A. Betts, Lara Cravo, Aarti Jagannath, Tirsa L.E. van Westering, Jinhong Meng, Katarzyna Chwalenia, Russell G. Foster, Jennifer E. Morgan, Carlo Rinaldi, Maria Sofia Falzarano, Elizabeth O’Donovan, Alessandra Ferlini, Graham McClorey, Katharina E. Meijboom, John R. Counsell, Amarjit Bhomra, Matthew J.A. Wood, Michael J. Gait, Amer F. Saleh, and Subhashis Banerjee
- Subjects
Serum Response Factor ,genetic structures ,Utrophin ,Myoblasts, Skeletal ,Health, Toxicology and Mutagenesis ,Plant Science ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Cell Line ,Dystrophin ,Mice ,Mediator ,Transcription (biology) ,medicine ,Animals ,Circadian rhythm ,Muscular dystrophy ,Research Articles ,Ecology ,biology ,Myogenesis ,Suprachiasmatic nucleus ,musculoskeletal system ,medicine.disease ,eye diseases ,Actins ,Cell biology ,embryonic structures ,cardiovascular system ,biology.protein ,medicine.symptom ,rhoA GTP-Binding Protein ,RC ,Signal Transduction ,Research Article ,Muscle contraction - Abstract
Absence of integral sarcolemmal protein, dystrophin, disrupts the RhoA-actin-SRF cascade in skeletal muscle, with subsequent dysregulation of downstream-SRF circadian targets and circadian rhythm., Absence of dystrophin, an essential sarcolemmal protein required for muscle contraction, leads to the devastating muscle-wasting disease Duchenne muscular dystrophy. Dystrophin has an actin-binding domain, which binds and stabilises filamentous-(F)-actin, an integral component of the RhoA-actin-serum-response-factor-(SRF) pathway. This pathway plays a crucial role in circadian signalling, whereby the suprachiasmatic nucleus (SCN) transmits cues to peripheral tissues, activating SRF and transcription of clock-target genes. Given dystrophin binds F-actin and disturbed SRF-signalling disrupts clock entrainment, we hypothesised dystrophin loss causes circadian deficits. We show for the first time alterations in the RhoA-actin-SRF-signalling pathway, in dystrophin-deficient myotubes and dystrophic mouse models. Specifically, we demonstrate reduced F/G-actin ratios, altered MRTF levels, dysregulated core-clock and downstream target-genes, and down-regulation of key circadian genes in muscle biopsies from Duchenne patients harbouring an array of mutations. Furthermore, we show dystrophin is absent in the SCN of dystrophic mice which display disrupted circadian locomotor behaviour, indicative of disrupted SCN signalling. Therefore, dystrophin is an important component of the RhoA-actin-SRF pathway and novel mediator of circadian signalling in peripheral tissues, loss of which leads to circadian dysregulation.
- Published
- 2021
8. Dystrophin regulates peripheral circadian SRF signalling
- Author
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Katarzyna Chwalenia, O'Donovan E, Russell G. Foster, Carlo Rinaldi, Graham McClorey, Soumya Banerjee, John R. Counsell, Jennifer E. Morgan, van Westering T, Saleh A, Lara Cravo, Jinhong Meng, Maria Sofia Falzarano, Melissa Bowerman, Matthew J.A. Wood, Corinne A. Betts, Lim C, Aarti Jagannath, Amarjit Bhomra, Gait Mj, Katharina E. Meijboom, and Ferlini A
- Subjects
musculoskeletal diseases ,Myogenesis ,Suprachiasmatic nucleus ,Biology ,musculoskeletal system ,medicine.disease ,Cell biology ,Mediator ,Transcription (biology) ,biology.protein ,medicine ,Circadian rhythm ,medicine.symptom ,Muscular dystrophy ,Dystrophin ,Muscle contraction - Abstract
Dystrophin is a sarcolemmal protein essential for muscle contraction and maintenance, absence of which leads to the devastating muscle wasting disease Duchenne muscular dystrophy (DMD)[1, 2]. Dystrophin has an actin-binding domain [3–5], which specifically binds and stabilises filamentous (F)-actin[6], an integral component of the RhoA-actin-serum response factor (SRF)-pathway[7]. The RhoA-actin-SRF-pathway plays an essential role in circadian signalling whereby the hypothalamic suprachiasmatic nucleus, transmits systemic cues to peripheral tissues, activating SRF and transcription of clock target genes[8, 9]. Given dystrophin binds F-actin and disturbed SRF-signalling disrupts clock entrainment, we hypothesised that dystrophin loss causes circadian deficits. Here we show for the first time alterations in the RhoA-actin-SRF-signalling-pathway, in both dystrophin-deficient myotubes and dystrophic mouse models. Specifically, we demonstrate reduced F/G-actin ratios and nuclear MRTF, dysregulation of core clock and downstream target-genes, and down-regulation of key circadian genes in muscle biopsies from DMD patients harbouring an array of mutations. Further, disrupted circadian locomotor behaviour was observed in dystrophic mice indicative of disrupted SCN signalling, and indeed dystrophin protein was absent in the SCN of dystrophic animals. Dystrophin is thus a critically important component of the RhoA-actin-SRF-pathway and a novel mediator of circadian signalling in peripheral tissues, loss of which leads to circadian dysregulation.
- Published
- 2021
9. Combining multiomics and drug perturbation profiles to identify muscle-specific treatments for spinal muscular atrophy
- Author
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Olivier G. de Jong, Nina Ahlskog, G Hazell, Katharina E. Meijboom, Caleb Webber, Joseph M. Hoolachan, Melissa Bowerman, Matthew J.A. Wood, Viola Volpato, Frank Abendroth, Suzan M. Hammond, Jimena Monzón-Sandoval, Afd Pharmaceutics, and Pharmaceutics
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Drug ,Proteomics ,RM ,Bioinformatics ,media_common.quotation_subject ,RS ,Transcriptome ,Muscular Atrophy, Spinal ,Mice ,Muscle pathology ,medicine ,Animals ,Humans ,Muscle, Skeletal ,Cells, Cultured ,media_common ,Medicine(all) ,business.industry ,Gene Expression Profiling ,Drug Repositioning ,Skeletal muscle ,Computational Biology ,General Medicine ,Spinal muscular atrophy ,Motor neuron ,SMA ,medicine.disease ,R1 ,Survival of Motor Neuron 1 Protein ,Disease Models, Animal ,Harmine ,medicine.anatomical_structure ,Neuromuscular Agents ,Muscle Biology ,Drug therapy ,business ,Research Article ,Neuroscience ,Genetic diseases - Abstract
Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by loss of survival motor neuron (SMN) protein. While SMN restoration therapies are beneficial, they are not a cure. We aimed to identify potentially novel treatments to alleviate muscle pathology combining transcriptomics, proteomics, and perturbational data sets. This revealed potential drug candidates for repurposing in SMA. One of the candidates, harmine, was further investigated in cell and animal models, improving multiple disease phenotypes, including lifespan, weight, and key molecular networks in skeletal muscle. Our work highlights the potential of multiple and parallel data-driven approaches for the development of potentially novel treatments for use in combination with SMN restoration therapies.
- Published
- 2021
10. Combining multi-omics and drug perturbation profiles to identify novel treatments that improve disease phenotypes in spinal muscular atrophy
- Author
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Jimena Monzón-Sandoval, Katharina E. Meijboom, Suzan M. Hammond, Melissa Bowerman, G Hazell, Viola Volpato, Joseph M. Hoolachan, Nina Ahlskog, Matthew J.A. Wood, Olivier G. de Jong, Caleb Webber, and Frank Abendroth
- Subjects
Drug ,business.industry ,animal diseases ,media_common.quotation_subject ,Spinal muscular atrophy ,Motor neuron ,Bioinformatics ,medicine.disease ,SMA ,Proteomics ,nervous system diseases ,Transcriptome ,medicine.anatomical_structure ,nervous system ,medicine ,Clinical phenotype ,business ,Repurposing ,media_common - Abstract
Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by loss of survival motor neuron (SMN) protein. While SMN restoration therapies are beneficial, they are not a cure. We aimed to identify novel treatments to alleviate muscle pathology combining transcriptomics, proteomics and perturbational datasets. This revealed potential drug candidates for repurposing in SMA. One of the lead candidates, harmine, was further investigated in cell and animal models, improving multiple disease phenotypes, including SMN expression and lifespan. Our work highlights the potential of multiple, parallel data driven approaches for development of novel treatments for use in combination with SMN restoration therapies.
- Published
- 2019
11. Light modulation ameliorates expression of circadian genes and disease progression in spinal muscular atrophy mice
- Author
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Peter Claus, van Westering Tle., Katharina E. Meijboom, Lisa Marie Walter, Amarjit Bhomra, Henrik Oster, Wood Mja., Nina Ahlskog, G Hazell, Christiane E Koch, Melissa Bowerman, and Corinne A. Betts
- Subjects
Male ,0301 basic medicine ,Light ,Biology ,Muscular Atrophy, Spinal ,Gene Knockout Techniques ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Genetics ,medicine ,Animals ,Circadian rhythm ,Molecular Biology ,Genetics (clinical) ,Regulation of gene expression ,General Medicine ,Spinal muscular atrophy ,Motor neuron ,medicine.disease ,SMA ,Survival of Motor Neuron 1 Protein ,R1 ,Circadian Rhythm ,CLOCK ,ARNTL ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Gene Expression Regulation ,Disease Progression ,Female ,General Article ,Neuroscience ,030217 neurology & neurosurgery ,PER1 - Abstract
Physiology and behaviour are critically dependent on circadian regulation via a core set of clock genes, dysregulation of which leads to metabolic and sleep disturbances. Metabolic and sleep perturbations occur in spinal muscular atrophy (SMA), a neuromuscular disorder caused by loss of the survival motor neuron (SMN) protein and characterized by motor neuron loss and muscle atrophy. We therefore investigated the expression of circadian rhythm genes in various metabolic tissues and spinal cord of the Taiwanese Smn−/−;SMN2 SMA animal model. We demonstrate a dysregulated expression of the core clock genes (clock, ARNTL/Bmal1, Cry1/2, Per1/2) and clock output genes (Nr1d1 and Dbp) in SMA tissues during disease progression. We also uncover an age- and tissue-dependent diurnal expression of the Smn gene. Importantly, we observe molecular and phenotypic corrections in SMA mice following direct light modulation. Our study identifies a key relationship between an SMA pathology and peripheral core clock gene dysregulation, highlights the influence of SMN on peripheral circadian regulation and metabolism and has significant implications for the development of peripheral therapeutic approaches and clinical care management of SMA patients.
- Published
- 2018
12. Interventions targeting glucocorticoid-Krüppel-like factor 15-branched-chain amino acid signaling improve disease phenotypes in spinal muscular atrophy mice
- Author
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Lyndsay M. Murray, Katharina E. Meijboom, Emily McFall, Tirsa L.E. van Westering, Suzan M. Hammond, Domenick A. Prosdocimo, Thomas H. Gillingwater, Marc-Olivier Deguise, Melissa Bowerman, Rashmi Kothary, Corinne A. Betts, Nina Ahlskog, G Hazell, Matthew J.A. Wood, Frank Abendroth, Hannah K. Shorrock, Anna Kordala, Mukesh K. Jain, Saptarsi M. Haldar, Lisa Marie Walter, and Peter Claus
- Subjects
0301 basic medicine ,Prednisolone ,Branched-chain amino acid ,Kruppel-Like Transcription Factors ,lcsh:Medicine ,KLF15 ,Bioinformatics ,General Biochemistry, Genetics and Molecular Biology ,Pathogenesis ,Muscular Atrophy, Spinal ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,medicine ,Animals ,Glucocorticoids ,Mice, Knockout ,lcsh:R5-920 ,business.industry ,lcsh:R ,Skeletal muscle ,General Medicine ,Spinal muscular atrophy ,SMA ,medicine.disease ,Branched-chain amino acids ,R1 ,3. Good health ,DNA-Binding Proteins ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Metabolism ,chemistry ,Dietary Supplements ,Therapy ,Signal transduction ,lcsh:Medicine (General) ,business ,030217 neurology & neurosurgery ,Glucocorticoid ,Amino Acids, Branched-Chain ,medicine.drug ,Research Paper ,Signal Transduction ,Transcription Factors - Abstract
The circadian glucocorticoid-Krüppel-like factor 15-branched-chain amino acid (GC-KLF15-BCAA) signaling pathway is a key regulatory axis in muscle, whose imbalance has wide-reaching effects on metabolic homeostasis. Spinal muscular atrophy (SMA) is a neuromuscular disorder also characterized by intrinsic muscle pathologies, metabolic abnormalities and disrupted sleep patterns, which can influence or be influenced by circadian regulatory networks that control behavioral and metabolic rhythms. We therefore set out to investigate the contribution of the GC-KLF15-BCAA pathway in SMA pathophysiology of Taiwanese Smn−/−;SMN2 and Smn2B/− mouse models. We thus uncover substantial dysregulation of GC-KLF15-BCAA diurnal rhythmicity in serum, skeletal muscle and metabolic tissues of SMA mice. Importantly, modulating the components of the GC-KLF15-BCAA pathway via pharmacological (prednisolone), genetic (muscle-specific Klf15 overexpression) and dietary (BCAA supplementation) interventions significantly improves disease phenotypes in SMA mice. Our study highlights the GC-KLF15-BCAA pathway as a contributor to SMA pathogenesis and provides several treatment avenues to alleviate peripheral manifestations of the disease. The therapeutic potential of targeting metabolic perturbations by diet and commercially available drugs could have a broader implementation across other neuromuscular and metabolic disorders characterized by altered GC-KLF15-BCAA signaling., Highlights • SMA is a neuromuscular disease characterized by motoneuron loss, muscle abnormalities and metabolic perturbations. • The regulatory GC-KLF15-BCAA pathway is dysregulated in serum and skeletal muscle of SMA mice during disease progression. • Modulating GC-KLF15-BCAA signaling by pharmacological, dietary and genetic interventions improves phenotype of SMA mice. Spinal muscular atrophy (SMA) is a devastating and debilitating childhood genetic disease. Although nerve cells are mainly affected, muscle is also severely impacted. The normal communication between the glucocorticoid (GC) hormone, the protein KLF15 and the dietary branched-chain amino acids (BCAAs) maintains muscle and whole-body health. In this study, we identified an abnormal activity of GC-KLF15- BCAA in blood and muscle of SMA mice. Importantly, targeting GC-KLF15-BCAA activity with an existing drug or a specific diet improved disease progression in SMA mice. Our research uncovers GCs, KLF15 and BCAAs as therapeutic targets to ameliorate SMA muscle and whole-body health.
- Published
- 2018
13. The glucocorticoid-KLF15-BCAA pathway as a novel therapeutic target for spinal muscular atrophy
- Author
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Rashmi Kothary, Katharina E. Meijboom, Melissa Bowerman, Corinne A. Betts, Marc-Olivier Deguise, Lisa Marie Walter, G Hazell, Emily McFall, Matthew J.A. Wood, and T.L.E. van Westering
- Subjects
medicine.medical_specialty ,business.industry ,Spinal muscular atrophy ,KLF15 ,medicine.disease ,Endocrinology ,Neurology ,Internal medicine ,Pediatrics, Perinatology and Child Health ,medicine ,Neurology (clinical) ,business ,Genetics (clinical) ,Glucocorticoid ,medicine.drug - Published
- 2017
14. The role of the TWEAK/Fn14 pathway in muscle pathology in SMA
- Author
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G Hazell, Emily McFall, Melissa Bowerman, Katharina E. Meijboom, Matthew J.A. Wood, Rashmi Kothary, Marc-Olivier Deguise, Daniel C. Anthony, and L.C. Burkly
- Subjects
Muscle pathology ,Neurology ,business.industry ,Pediatrics, Perinatology and Child Health ,Medicine ,Neurology (clinical) ,Anatomy ,SMA ,business ,Genetics (clinical) - Published
- 2017
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