A potential therapeutic effect of catalpol in Duchenne muscular dystrophy revealed by binding with TAK1
Background Duchenne muscular dystrophy (DMD) is a progressive muscle disease caused by the loss of dystrophin, which results in inflammation, fibrosis, and the inhibition of myoblast differentiation in skeletal muscle. Catalpol, an iridoid glycoside, improves skeletal muscle function by enhancing my...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2020-10-01
|
| Series: | Journal of Cachexia, Sarcopenia and Muscle |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/jcsm.12581 |
| _version_ | 1797203648813465600 |
|---|---|
| author | Dengqiu Xu Lei Zhao Jingwei Jiang Sijia Li Zeren Sun Xiaofei Huang Chunjie Li Tao Wang Lixin Sun Xihua Li Zhenzhou Jiang Luyong Zhang |
| author_facet | Dengqiu Xu Lei Zhao Jingwei Jiang Sijia Li Zeren Sun Xiaofei Huang Chunjie Li Tao Wang Lixin Sun Xihua Li Zhenzhou Jiang Luyong Zhang |
| author_sort | Dengqiu Xu |
| collection | DOAJ |
| description | Background Duchenne muscular dystrophy (DMD) is a progressive muscle disease caused by the loss of dystrophin, which results in inflammation, fibrosis, and the inhibition of myoblast differentiation in skeletal muscle. Catalpol, an iridoid glycoside, improves skeletal muscle function by enhancing myogenesis; it has potential to treat DMD. We demonstrate the positive effects of catalpol in dystrophic skeletal muscle. Methods mdx (loss of dystrophin) mice (n = 18 per group) were treated with catalpol (200 mg/kg) for six consecutive weeks. Serum analysis, skeletal muscle performance and histology, muscle contractile function, and gene and protein expression were performed. Molecular docking and ligand–target interactions, RNA interference, immunofluorescence, and plasmids transfection were utilized to explore the protective mechanism in DMD by which catalpol binding with transforming growth factor‐β–activated kinase 1 (TAK1) in skeletal muscle. Results Six weeks of catalpol treatment improved whole‐body muscle health in mdx mice, which was characterized by reduced plasma creatine kinase (n = 18, −35.1%, P < 0.05) and lactic dehydrogenase (n = 18, −10.3%, P < 0.05) activity. These effects were accompanied by enhanced grip strength (n = 18, +25.4%, P < 0.05) and reduced fibrosis (n = 18, −29.0% for hydroxyproline content, P < 0.05). Moreover, catalpol treatment protected against muscle fatigue and promoted muscle recovery in the tibialis anterior (TA) and diaphragm (DIA) muscles (n = 6, +69.8%, P < 0.05 and + 74.8%, P < 0.001, respectively), which was accompanied by enhanced differentiation in primary myoblasts from DMD patients (n = 6, male, mean age: 4.7 ± 1.9 years) and mdx mice. In addition, catalpol eliminated p‐TAK1 overexpression in mdx mice (n = 12, −21.3%, P < 0.05) and primary myoblasts. The catalpol‐induced reduction in fibrosis and increased myoblast differentiation resulted from the inhibition of TAK1 phosphorylation, leading to reduced myoblast trans‐differentiation into myofibroblasts. Catalpol inhibited the phosphorylation of TAK1 by binding to TAK1, possibly at Asp‐206, Thr‐208, Asn‐211, Glu‐297, Lys‐294, and Tyr‐293. Conclusions Our findings show that catalpol and TAK1 inhibitors substantially improve whole‐body muscle health and the function of dystrophic skeletal muscles and may provide a novel therapy for DMD. |
| first_indexed | 2024-04-24T08:22:41Z |
| format | Article |
| id | doaj.art-887ee74267ff40d29395a0f2e459507d |
| institution | Directory Open Access Journal |
| issn | 2190-5991 2190-6009 |
| language | English |
| last_indexed | 2024-04-24T08:22:41Z |
| publishDate | 2020-10-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Cachexia, Sarcopenia and Muscle |
| spelling | doaj.art-887ee74267ff40d29395a0f2e459507d2024-04-17T00:07:32ZengWileyJournal of Cachexia, Sarcopenia and Muscle2190-59912190-60092020-10-011151306132010.1002/jcsm.12581A potential therapeutic effect of catalpol in Duchenne muscular dystrophy revealed by binding with TAK1Dengqiu Xu0Lei Zhao1Jingwei Jiang2Sijia Li3Zeren Sun4Xiaofei Huang5Chunjie Li6Tao Wang7Lixin Sun8Xihua Li9Zhenzhou Jiang10Luyong Zhang11Jiangsu Key Laboratory of Drug Screening China Pharmaceutical University Nanjing ChinaDepartment of Neurology Children's Hospital of Fudan University Shanghai ChinaJiangsu Key Laboratory of Drug Screening China Pharmaceutical University Nanjing ChinaJiangsu Key Laboratory of Drug Screening China Pharmaceutical University Nanjing ChinaJiangsu Key Laboratory of Drug Screening China Pharmaceutical University Nanjing ChinaJiangsu Key Laboratory of Drug Screening China Pharmaceutical University Nanjing ChinaJiangsu Key Laboratory of Drug Screening China Pharmaceutical University Nanjing ChinaJiangsu Key Laboratory of Drug Screening China Pharmaceutical University Nanjing ChinaJiangsu Key Laboratory of Drug Screening China Pharmaceutical University Nanjing ChinaDepartment of Neurology Children's Hospital of Fudan University Shanghai ChinaJiangsu Key Laboratory of Drug Screening China Pharmaceutical University Nanjing ChinaJiangsu Key Laboratory of Drug Screening China Pharmaceutical University Nanjing ChinaBackground Duchenne muscular dystrophy (DMD) is a progressive muscle disease caused by the loss of dystrophin, which results in inflammation, fibrosis, and the inhibition of myoblast differentiation in skeletal muscle. Catalpol, an iridoid glycoside, improves skeletal muscle function by enhancing myogenesis; it has potential to treat DMD. We demonstrate the positive effects of catalpol in dystrophic skeletal muscle. Methods mdx (loss of dystrophin) mice (n = 18 per group) were treated with catalpol (200 mg/kg) for six consecutive weeks. Serum analysis, skeletal muscle performance and histology, muscle contractile function, and gene and protein expression were performed. Molecular docking and ligand–target interactions, RNA interference, immunofluorescence, and plasmids transfection were utilized to explore the protective mechanism in DMD by which catalpol binding with transforming growth factor‐β–activated kinase 1 (TAK1) in skeletal muscle. Results Six weeks of catalpol treatment improved whole‐body muscle health in mdx mice, which was characterized by reduced plasma creatine kinase (n = 18, −35.1%, P < 0.05) and lactic dehydrogenase (n = 18, −10.3%, P < 0.05) activity. These effects were accompanied by enhanced grip strength (n = 18, +25.4%, P < 0.05) and reduced fibrosis (n = 18, −29.0% for hydroxyproline content, P < 0.05). Moreover, catalpol treatment protected against muscle fatigue and promoted muscle recovery in the tibialis anterior (TA) and diaphragm (DIA) muscles (n = 6, +69.8%, P < 0.05 and + 74.8%, P < 0.001, respectively), which was accompanied by enhanced differentiation in primary myoblasts from DMD patients (n = 6, male, mean age: 4.7 ± 1.9 years) and mdx mice. In addition, catalpol eliminated p‐TAK1 overexpression in mdx mice (n = 12, −21.3%, P < 0.05) and primary myoblasts. The catalpol‐induced reduction in fibrosis and increased myoblast differentiation resulted from the inhibition of TAK1 phosphorylation, leading to reduced myoblast trans‐differentiation into myofibroblasts. Catalpol inhibited the phosphorylation of TAK1 by binding to TAK1, possibly at Asp‐206, Thr‐208, Asn‐211, Glu‐297, Lys‐294, and Tyr‐293. Conclusions Our findings show that catalpol and TAK1 inhibitors substantially improve whole‐body muscle health and the function of dystrophic skeletal muscles and may provide a novel therapy for DMD.https://doi.org/10.1002/jcsm.12581TAK1Duchenne muscular dystrophyCatalpolFibrosisMyogenesis |
| spellingShingle | Dengqiu Xu Lei Zhao Jingwei Jiang Sijia Li Zeren Sun Xiaofei Huang Chunjie Li Tao Wang Lixin Sun Xihua Li Zhenzhou Jiang Luyong Zhang A potential therapeutic effect of catalpol in Duchenne muscular dystrophy revealed by binding with TAK1 Journal of Cachexia, Sarcopenia and Muscle TAK1 Duchenne muscular dystrophy Catalpol Fibrosis Myogenesis |
| title | A potential therapeutic effect of catalpol in Duchenne muscular dystrophy revealed by binding with TAK1 |
| title_full | A potential therapeutic effect of catalpol in Duchenne muscular dystrophy revealed by binding with TAK1 |
| title_fullStr | A potential therapeutic effect of catalpol in Duchenne muscular dystrophy revealed by binding with TAK1 |
| title_full_unstemmed | A potential therapeutic effect of catalpol in Duchenne muscular dystrophy revealed by binding with TAK1 |
| title_short | A potential therapeutic effect of catalpol in Duchenne muscular dystrophy revealed by binding with TAK1 |
| title_sort | potential therapeutic effect of catalpol in duchenne muscular dystrophy revealed by binding with tak1 |
| topic | TAK1 Duchenne muscular dystrophy Catalpol Fibrosis Myogenesis |
| url | https://doi.org/10.1002/jcsm.12581 |
| work_keys_str_mv | AT dengqiuxu apotentialtherapeuticeffectofcatalpolinduchennemusculardystrophyrevealedbybindingwithtak1 AT leizhao apotentialtherapeuticeffectofcatalpolinduchennemusculardystrophyrevealedbybindingwithtak1 AT jingweijiang apotentialtherapeuticeffectofcatalpolinduchennemusculardystrophyrevealedbybindingwithtak1 AT sijiali apotentialtherapeuticeffectofcatalpolinduchennemusculardystrophyrevealedbybindingwithtak1 AT zerensun apotentialtherapeuticeffectofcatalpolinduchennemusculardystrophyrevealedbybindingwithtak1 AT xiaofeihuang apotentialtherapeuticeffectofcatalpolinduchennemusculardystrophyrevealedbybindingwithtak1 AT chunjieli apotentialtherapeuticeffectofcatalpolinduchennemusculardystrophyrevealedbybindingwithtak1 AT taowang apotentialtherapeuticeffectofcatalpolinduchennemusculardystrophyrevealedbybindingwithtak1 AT lixinsun apotentialtherapeuticeffectofcatalpolinduchennemusculardystrophyrevealedbybindingwithtak1 AT xihuali apotentialtherapeuticeffectofcatalpolinduchennemusculardystrophyrevealedbybindingwithtak1 AT zhenzhoujiang apotentialtherapeuticeffectofcatalpolinduchennemusculardystrophyrevealedbybindingwithtak1 AT luyongzhang apotentialtherapeuticeffectofcatalpolinduchennemusculardystrophyrevealedbybindingwithtak1 AT dengqiuxu potentialtherapeuticeffectofcatalpolinduchennemusculardystrophyrevealedbybindingwithtak1 AT leizhao potentialtherapeuticeffectofcatalpolinduchennemusculardystrophyrevealedbybindingwithtak1 AT jingweijiang potentialtherapeuticeffectofcatalpolinduchennemusculardystrophyrevealedbybindingwithtak1 AT sijiali potentialtherapeuticeffectofcatalpolinduchennemusculardystrophyrevealedbybindingwithtak1 AT zerensun potentialtherapeuticeffectofcatalpolinduchennemusculardystrophyrevealedbybindingwithtak1 AT xiaofeihuang potentialtherapeuticeffectofcatalpolinduchennemusculardystrophyrevealedbybindingwithtak1 AT chunjieli potentialtherapeuticeffectofcatalpolinduchennemusculardystrophyrevealedbybindingwithtak1 AT taowang potentialtherapeuticeffectofcatalpolinduchennemusculardystrophyrevealedbybindingwithtak1 AT lixinsun potentialtherapeuticeffectofcatalpolinduchennemusculardystrophyrevealedbybindingwithtak1 AT xihuali potentialtherapeuticeffectofcatalpolinduchennemusculardystrophyrevealedbybindingwithtak1 AT zhenzhoujiang potentialtherapeuticeffectofcatalpolinduchennemusculardystrophyrevealedbybindingwithtak1 AT luyongzhang potentialtherapeuticeffectofcatalpolinduchennemusculardystrophyrevealedbybindingwithtak1 |