Skeletal Muscle Atrophy Induced by Diabetes Is Mediated by Non-Selective Channels and Prevented by Boldine
Individuals with diabetes mellitus present a skeletal muscle myopathy characterized by atrophy. However, the mechanism underlying this muscular alteration remains elusive, which makes it difficult to design a rational treatment that could avoid the negative consequences in muscles due to diabetes. I...
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MDPI AG
2023-04-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/13/4/708 |
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| author | Luis A. Cea Walter Vásquez Romina Hernández-Salinas Alejandra Z. Vielma Mario Castillo-Ruiz Victoria Velarde Magdiel Salgado Juan C. Sáez |
| author_facet | Luis A. Cea Walter Vásquez Romina Hernández-Salinas Alejandra Z. Vielma Mario Castillo-Ruiz Victoria Velarde Magdiel Salgado Juan C. Sáez |
| author_sort | Luis A. Cea |
| collection | DOAJ |
| description | Individuals with diabetes mellitus present a skeletal muscle myopathy characterized by atrophy. However, the mechanism underlying this muscular alteration remains elusive, which makes it difficult to design a rational treatment that could avoid the negative consequences in muscles due to diabetes. In the present work, the atrophy of skeletal myofibers from streptozotocin-induced diabetic rats was prevented with boldine, suggesting that non-selective channels inhibited by this alkaloid are involved in this process, as has previously shown for other muscular pathologies. Accordingly, we found a relevant increase in sarcolemma permeability of skeletal myofibers of diabetic animals in vivo and in vitro due to de novo expression of functional connexin hemichannels (Cx HCs) containing connexins (Cxs) 39, 43, and 45. These cells also expressed P2X<sub>7</sub> receptors, and their inhibition in vitro drastically reduced sarcolemma permeability, suggesting their participation in the activation of Cx HCs. Notably, sarcolemma permeability of skeletal myofibers was prevented by boldine treatment that blocks Cx43 and Cx45 HCs, and now we demonstrated that it also blocks P2X<sub>7</sub> receptors. In addition, the skeletal muscle alterations described above were not observed in diabetic mice with myofibers deficient in Cx43/Cx45 expression. Moreover, murine myofibers cultured for 24 h in high glucose presented a drastic increase in sarcolemma permeability and levels of NLRP3, a molecular member of the inflammasome, a response that was also prevented by boldine, suggesting that, in addition to the systemic inflammatory response found in diabetes, high glucose can promote the expression of functional Cx HCs and activation of the inflammasome in skeletal myofibers. Therefore, Cx43 and Cx45 HCs play a critical role in myofiber degeneration, and boldine could be considered a potential therapeutic agent to treat muscular complications due to diabetes. |
| first_indexed | 2024-03-11T05:12:12Z |
| format | Article |
| id | doaj.art-9e39fb2e13d94391a179a6bf37f6ca23 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-11T05:12:12Z |
| publishDate | 2023-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-9e39fb2e13d94391a179a6bf37f6ca232023-11-17T18:30:12ZengMDPI AGBiomolecules2218-273X2023-04-0113470810.3390/biom13040708Skeletal Muscle Atrophy Induced by Diabetes Is Mediated by Non-Selective Channels and Prevented by BoldineLuis A. Cea0Walter Vásquez1Romina Hernández-Salinas2Alejandra Z. Vielma3Mario Castillo-Ruiz4Victoria Velarde5Magdiel Salgado6Juan C. Sáez7Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Av. Llano Subercaseaux 2801, San Miguel, Santiago 8910060, ChileDepartamento de Fisiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8330024, ChileCentro de Fisiología Celular e Integrativa, Facultad de Medicina, Universidad del Desarrollo, Santiago 7610000, ChileEscuela de Odontología, Facultad de Medicina Clínica Alemana, Universidad del Desarrollo, Santiago 7610000, ChileEscuela de Química y Farmacia, Facultad de Medicina, Universidad Andres Bello, Santiago 8370149, ChileInstituto de Fisiología, Universidad de Valparaíso, Valparaíso 2340000, ChileInstituto de Neurociencias, Centro Interdisciplinario de Neurociencias de Valparaíso, Universidad de Valparaíso, Pasaje Harrington 287, Playa Ancha, Valparaíso 2340000, ChileInstituto de Neurociencias, Centro Interdisciplinario de Neurociencias de Valparaíso, Universidad de Valparaíso, Pasaje Harrington 287, Playa Ancha, Valparaíso 2340000, ChileIndividuals with diabetes mellitus present a skeletal muscle myopathy characterized by atrophy. However, the mechanism underlying this muscular alteration remains elusive, which makes it difficult to design a rational treatment that could avoid the negative consequences in muscles due to diabetes. In the present work, the atrophy of skeletal myofibers from streptozotocin-induced diabetic rats was prevented with boldine, suggesting that non-selective channels inhibited by this alkaloid are involved in this process, as has previously shown for other muscular pathologies. Accordingly, we found a relevant increase in sarcolemma permeability of skeletal myofibers of diabetic animals in vivo and in vitro due to de novo expression of functional connexin hemichannels (Cx HCs) containing connexins (Cxs) 39, 43, and 45. These cells also expressed P2X<sub>7</sub> receptors, and their inhibition in vitro drastically reduced sarcolemma permeability, suggesting their participation in the activation of Cx HCs. Notably, sarcolemma permeability of skeletal myofibers was prevented by boldine treatment that blocks Cx43 and Cx45 HCs, and now we demonstrated that it also blocks P2X<sub>7</sub> receptors. In addition, the skeletal muscle alterations described above were not observed in diabetic mice with myofibers deficient in Cx43/Cx45 expression. Moreover, murine myofibers cultured for 24 h in high glucose presented a drastic increase in sarcolemma permeability and levels of NLRP3, a molecular member of the inflammasome, a response that was also prevented by boldine, suggesting that, in addition to the systemic inflammatory response found in diabetes, high glucose can promote the expression of functional Cx HCs and activation of the inflammasome in skeletal myofibers. Therefore, Cx43 and Cx45 HCs play a critical role in myofiber degeneration, and boldine could be considered a potential therapeutic agent to treat muscular complications due to diabetes.https://www.mdpi.com/2218-273X/13/4/708sarcolemma permeabilityconnexinscalcium atrophyhemichannel blocker |
| spellingShingle | Luis A. Cea Walter Vásquez Romina Hernández-Salinas Alejandra Z. Vielma Mario Castillo-Ruiz Victoria Velarde Magdiel Salgado Juan C. Sáez Skeletal Muscle Atrophy Induced by Diabetes Is Mediated by Non-Selective Channels and Prevented by Boldine Biomolecules sarcolemma permeability connexins calcium atrophy hemichannel blocker |
| title | Skeletal Muscle Atrophy Induced by Diabetes Is Mediated by Non-Selective Channels and Prevented by Boldine |
| title_full | Skeletal Muscle Atrophy Induced by Diabetes Is Mediated by Non-Selective Channels and Prevented by Boldine |
| title_fullStr | Skeletal Muscle Atrophy Induced by Diabetes Is Mediated by Non-Selective Channels and Prevented by Boldine |
| title_full_unstemmed | Skeletal Muscle Atrophy Induced by Diabetes Is Mediated by Non-Selective Channels and Prevented by Boldine |
| title_short | Skeletal Muscle Atrophy Induced by Diabetes Is Mediated by Non-Selective Channels and Prevented by Boldine |
| title_sort | skeletal muscle atrophy induced by diabetes is mediated by non selective channels and prevented by boldine |
| topic | sarcolemma permeability connexins calcium atrophy hemichannel blocker |
| url | https://www.mdpi.com/2218-273X/13/4/708 |
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