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Amelioration of diabetes‐induced inflammation mediated pyroptosis, sarcopenia, and adverse muscle remodelling by bone morphogenetic protein‐7

BACKGROUND: Diabetic myopathy involves hyperglycaemia and inflammation that causes skeletal muscle dysfunction; however, the potential cellular mechanisms that occur between hyperglycaemia and inflammation, which induces sarcopenia, and muscle dysfunction remain unknown. In this study, we investigat...

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Autores principales: Aluganti Narasimhulu, Chandrakala, Singla, Dinender K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061343/
https://www.ncbi.nlm.nih.gov/pubmed/33463042
http://dx.doi.org/10.1002/jcsm.12662
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author Aluganti Narasimhulu, Chandrakala
Singla, Dinender K.
author_facet Aluganti Narasimhulu, Chandrakala
Singla, Dinender K.
author_sort Aluganti Narasimhulu, Chandrakala
collection PubMed
description BACKGROUND: Diabetic myopathy involves hyperglycaemia and inflammation that causes skeletal muscle dysfunction; however, the potential cellular mechanisms that occur between hyperglycaemia and inflammation, which induces sarcopenia, and muscle dysfunction remain unknown. In this study, we investigated hyperglycaemia‐induced inflammation mediating high‐mobility group box 1 activation, which is involved in a novel form of cell death, pyroptosis, diabetic sarcopenia, atrophy, and adverse muscle remodelling. Furthermore, we investigated the therapeutic potential of bone morphogenetic protein‐7 (BMP‐7), an osteoporosis drug, to treat pyroptosis, and diabetic muscle myopathy. METHODS: C57BL6 mice were treated with saline (control), streptozotocin (STZ), or STZ + BMP‐7 to generate diabetic muscle myopathy. Diabetes was established by determining the increased levels of glucose. Then, muscle function was examined, and animals were sacrificed. Gastrocnemius muscle or blood samples were analysed for inflammation, pyroptosis, weight loss, muscle atrophy, and adverse structural remodelling of gastrocnemius muscle using histology, enzyme‐linked immunosorbent assay, immunohistochemistry, western blotting, and reverse transcription polymerase chain reaction. RESULTS: A significant (P < 0.05) increase in hyperglycaemia leads to an increase in inflammasome (high‐mobility group box 1, toll‐like receptor‐4, and nucleotide‐binding oligomerization domain, leucine‐rich repeat and pyrin domain containing protein 3) formation in diabetic muscle cells. Further analysis showed an up‐regulation of the downstream pyroptotic pathway with significant (P < 0.05) number of positive muscle cells expressing pyroptosis‐specific markers [caspase‐1, interleukin (IL)‐1β, IL‐18, and gasdermin‐D]. Pyroptotic cell death is involved in further increasing inflammation by releasing pro‐inflammatory cytokine IL‐6. Structural analysis showed the loss of muscle weight, decreased myofibrillar area, and increased fibrosis leading to muscle dysfunction. Consistent with this finding, BMP‐7 attenuated hyperglycaemia (~50%), pyroptosis, inflammation, and diabetic adverse structural modifications as well as improved muscle function. CONCLUSIONS: In conclusion, we report for the first time that increased hyperglycaemia and inflammation involve cellular pyroptosis that induces significant muscle cell loss and adverse remodelling in diabetic myopathy. We also report that targeting pyroptosis with BMP‐7 improves diabetic muscle pathophysiology and muscle function. These findings suggest that BMP‐7 could be a potential therapeutic option to treat diabetic myopathy.
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spelling pubmed-80613432021-04-23 Amelioration of diabetes‐induced inflammation mediated pyroptosis, sarcopenia, and adverse muscle remodelling by bone morphogenetic protein‐7 Aluganti Narasimhulu, Chandrakala Singla, Dinender K. J Cachexia Sarcopenia Muscle Original Articles BACKGROUND: Diabetic myopathy involves hyperglycaemia and inflammation that causes skeletal muscle dysfunction; however, the potential cellular mechanisms that occur between hyperglycaemia and inflammation, which induces sarcopenia, and muscle dysfunction remain unknown. In this study, we investigated hyperglycaemia‐induced inflammation mediating high‐mobility group box 1 activation, which is involved in a novel form of cell death, pyroptosis, diabetic sarcopenia, atrophy, and adverse muscle remodelling. Furthermore, we investigated the therapeutic potential of bone morphogenetic protein‐7 (BMP‐7), an osteoporosis drug, to treat pyroptosis, and diabetic muscle myopathy. METHODS: C57BL6 mice were treated with saline (control), streptozotocin (STZ), or STZ + BMP‐7 to generate diabetic muscle myopathy. Diabetes was established by determining the increased levels of glucose. Then, muscle function was examined, and animals were sacrificed. Gastrocnemius muscle or blood samples were analysed for inflammation, pyroptosis, weight loss, muscle atrophy, and adverse structural remodelling of gastrocnemius muscle using histology, enzyme‐linked immunosorbent assay, immunohistochemistry, western blotting, and reverse transcription polymerase chain reaction. RESULTS: A significant (P < 0.05) increase in hyperglycaemia leads to an increase in inflammasome (high‐mobility group box 1, toll‐like receptor‐4, and nucleotide‐binding oligomerization domain, leucine‐rich repeat and pyrin domain containing protein 3) formation in diabetic muscle cells. Further analysis showed an up‐regulation of the downstream pyroptotic pathway with significant (P < 0.05) number of positive muscle cells expressing pyroptosis‐specific markers [caspase‐1, interleukin (IL)‐1β, IL‐18, and gasdermin‐D]. Pyroptotic cell death is involved in further increasing inflammation by releasing pro‐inflammatory cytokine IL‐6. Structural analysis showed the loss of muscle weight, decreased myofibrillar area, and increased fibrosis leading to muscle dysfunction. Consistent with this finding, BMP‐7 attenuated hyperglycaemia (~50%), pyroptosis, inflammation, and diabetic adverse structural modifications as well as improved muscle function. CONCLUSIONS: In conclusion, we report for the first time that increased hyperglycaemia and inflammation involve cellular pyroptosis that induces significant muscle cell loss and adverse remodelling in diabetic myopathy. We also report that targeting pyroptosis with BMP‐7 improves diabetic muscle pathophysiology and muscle function. These findings suggest that BMP‐7 could be a potential therapeutic option to treat diabetic myopathy. John Wiley and Sons Inc. 2021-01-18 2021-04 /pmc/articles/PMC8061343/ /pubmed/33463042 http://dx.doi.org/10.1002/jcsm.12662 Text en © 2021 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Aluganti Narasimhulu, Chandrakala
Singla, Dinender K.
Amelioration of diabetes‐induced inflammation mediated pyroptosis, sarcopenia, and adverse muscle remodelling by bone morphogenetic protein‐7
title Amelioration of diabetes‐induced inflammation mediated pyroptosis, sarcopenia, and adverse muscle remodelling by bone morphogenetic protein‐7
title_full Amelioration of diabetes‐induced inflammation mediated pyroptosis, sarcopenia, and adverse muscle remodelling by bone morphogenetic protein‐7
title_fullStr Amelioration of diabetes‐induced inflammation mediated pyroptosis, sarcopenia, and adverse muscle remodelling by bone morphogenetic protein‐7
title_full_unstemmed Amelioration of diabetes‐induced inflammation mediated pyroptosis, sarcopenia, and adverse muscle remodelling by bone morphogenetic protein‐7
title_short Amelioration of diabetes‐induced inflammation mediated pyroptosis, sarcopenia, and adverse muscle remodelling by bone morphogenetic protein‐7
title_sort amelioration of diabetes‐induced inflammation mediated pyroptosis, sarcopenia, and adverse muscle remodelling by bone morphogenetic protein‐7
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061343/
https://www.ncbi.nlm.nih.gov/pubmed/33463042
http://dx.doi.org/10.1002/jcsm.12662
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