Exercise mitigates Dapagliflozin-induced skeletal muscle atrophy in STZ-induced diabetic rats

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are commonly used in the management of type 2 diabetes mellitus (T2DM) and have been found to worsen the reduction of skeletal muscle mass in individuals with T2DM. This study aims to examine the potential of exercise in mitigating the s...

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Autores principales: Yang, Xudong, Wang, Lifeng, Zhang, Liangzhi, Zhai, Xia, Sheng, Xiusheng, Quan, Helong, Lin, Hengjun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10337193/
https://www.ncbi.nlm.nih.gov/pubmed/37438792
http://dx.doi.org/10.1186/s13098-023-01130-w
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author Yang, Xudong
Wang, Lifeng
Zhang, Liangzhi
Zhai, Xia
Sheng, Xiusheng
Quan, Helong
Lin, Hengjun
author_facet Yang, Xudong
Wang, Lifeng
Zhang, Liangzhi
Zhai, Xia
Sheng, Xiusheng
Quan, Helong
Lin, Hengjun
author_sort Yang, Xudong
collection PubMed
description BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are commonly used in the management of type 2 diabetes mellitus (T2DM) and have been found to worsen the reduction of skeletal muscle mass in individuals with T2DM. This study aims to examine the potential of exercise in mitigating the skeletal muscle atrophy induced by SGLT2i treatment. METHODS: A rat model of T2DM (40 male Sprague-Dawley rats; T2DM induced by a combination of high-fat diet and streptozotocin) was used to examine the effects of six-week treatment with Dapagliflozin (DAPA, SGLT2i) in combination with either aerobic exercise (AE) or resistance training (RT) on skeletal muscle. T2DM-eligible rats were randomized into the T2DM control group (CON, n = 6), DAPA treatment group (DAPA, n = 6), DAPA combined with aerobic exercise intervention group (DAPA + AE, n = 6), and DAPA combined with resistance training intervention group (DAPA + RT, n = 6). To assess the morphological changes in skeletal muscle, myosin ATPase and HE staining were performed. mRNA expression levels of Atrogin-1, MuRF1, and Myostatin were determined using quantitative PCR. Furthermore, protein expression levels of AKT, p70S6K, mTOR, FoXO1/3A, NF-κB, and MuRF1 were examined through western blotting. RESULTS: Both the administration of DAPA alone and the combined exercise intervention with DAPA resulted in significant reductions in blood glucose levels and body weight in rats. However, DAPA alone administration led to a decrease in skeletal muscle mass, whereas RT significantly increased skeletal muscle mass and muscle fiber cross-sectional area. The DAPA + RT group exhibited notable increases in both total protein levels and phosphorylation levels of AKT and p70S6K in skeletal muscle. Moreover, the DAPA, DAPA + AE, and DAPA + RT groups demonstrated downregulation of protein expression (FoXO1/3A) and mRNA levels (Atrogin-1, MuRF1, and Myostatin) associated with muscle atrophy. CONCLUSIONS: Our findings provide support for the notion that dapagliflozin may induce skeletal muscle atrophy through mechanisms unrelated to protein metabolism impairment in skeletal muscle, as it does not hinder protein metabolic pathways while reduces muscle atrophy-related genes. Additionally, our observations reveal that RT proves more effective than AE in enhancing skeletal muscle mass and muscle fiber cross-sectional area in rats with T2DM by stimulating protein anabolism within the skeletal muscle. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13098-023-01130-w.
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spelling pubmed-103371932023-07-13 Exercise mitigates Dapagliflozin-induced skeletal muscle atrophy in STZ-induced diabetic rats Yang, Xudong Wang, Lifeng Zhang, Liangzhi Zhai, Xia Sheng, Xiusheng Quan, Helong Lin, Hengjun Diabetol Metab Syndr Research BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are commonly used in the management of type 2 diabetes mellitus (T2DM) and have been found to worsen the reduction of skeletal muscle mass in individuals with T2DM. This study aims to examine the potential of exercise in mitigating the skeletal muscle atrophy induced by SGLT2i treatment. METHODS: A rat model of T2DM (40 male Sprague-Dawley rats; T2DM induced by a combination of high-fat diet and streptozotocin) was used to examine the effects of six-week treatment with Dapagliflozin (DAPA, SGLT2i) in combination with either aerobic exercise (AE) or resistance training (RT) on skeletal muscle. T2DM-eligible rats were randomized into the T2DM control group (CON, n = 6), DAPA treatment group (DAPA, n = 6), DAPA combined with aerobic exercise intervention group (DAPA + AE, n = 6), and DAPA combined with resistance training intervention group (DAPA + RT, n = 6). To assess the morphological changes in skeletal muscle, myosin ATPase and HE staining were performed. mRNA expression levels of Atrogin-1, MuRF1, and Myostatin were determined using quantitative PCR. Furthermore, protein expression levels of AKT, p70S6K, mTOR, FoXO1/3A, NF-κB, and MuRF1 were examined through western blotting. RESULTS: Both the administration of DAPA alone and the combined exercise intervention with DAPA resulted in significant reductions in blood glucose levels and body weight in rats. However, DAPA alone administration led to a decrease in skeletal muscle mass, whereas RT significantly increased skeletal muscle mass and muscle fiber cross-sectional area. The DAPA + RT group exhibited notable increases in both total protein levels and phosphorylation levels of AKT and p70S6K in skeletal muscle. Moreover, the DAPA, DAPA + AE, and DAPA + RT groups demonstrated downregulation of protein expression (FoXO1/3A) and mRNA levels (Atrogin-1, MuRF1, and Myostatin) associated with muscle atrophy. CONCLUSIONS: Our findings provide support for the notion that dapagliflozin may induce skeletal muscle atrophy through mechanisms unrelated to protein metabolism impairment in skeletal muscle, as it does not hinder protein metabolic pathways while reduces muscle atrophy-related genes. Additionally, our observations reveal that RT proves more effective than AE in enhancing skeletal muscle mass and muscle fiber cross-sectional area in rats with T2DM by stimulating protein anabolism within the skeletal muscle. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13098-023-01130-w. BioMed Central 2023-07-12 /pmc/articles/PMC10337193/ /pubmed/37438792 http://dx.doi.org/10.1186/s13098-023-01130-w Text en © The Author(s) 2023, corrected publication 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Yang, Xudong
Wang, Lifeng
Zhang, Liangzhi
Zhai, Xia
Sheng, Xiusheng
Quan, Helong
Lin, Hengjun
Exercise mitigates Dapagliflozin-induced skeletal muscle atrophy in STZ-induced diabetic rats
title Exercise mitigates Dapagliflozin-induced skeletal muscle atrophy in STZ-induced diabetic rats
title_full Exercise mitigates Dapagliflozin-induced skeletal muscle atrophy in STZ-induced diabetic rats
title_fullStr Exercise mitigates Dapagliflozin-induced skeletal muscle atrophy in STZ-induced diabetic rats
title_full_unstemmed Exercise mitigates Dapagliflozin-induced skeletal muscle atrophy in STZ-induced diabetic rats
title_short Exercise mitigates Dapagliflozin-induced skeletal muscle atrophy in STZ-induced diabetic rats
title_sort exercise mitigates dapagliflozin-induced skeletal muscle atrophy in stz-induced diabetic rats
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10337193/
https://www.ncbi.nlm.nih.gov/pubmed/37438792
http://dx.doi.org/10.1186/s13098-023-01130-w
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