Indoprofen prevents muscle wasting in aged mice through activation of PDK1/AKT pathway
Abstract Background Muscle wasting, resulting from aging or pathological conditions, leads to reduced quality of life, increased morbidity, and increased mortality. Much research effort has been focused on the development of exercise mimetics to prevent muscle atrophy and weakness. In this study, we...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2020-08-01
|
| Series: | Journal of Cachexia, Sarcopenia and Muscle |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/jcsm.12558 |
| _version_ | 1797204094486577152 |
|---|---|
| author | Hyebeen Kim Sung Chun Cho Hyeon‐Ju Jeong Hye‐Young Lee Myong‐Ho Jeong Jung‐Hoon Pyun Dongryeol Ryu MinSeok Kim Young‐Sam Lee Minseok S. Kim Sang Chul Park Yun‐Il Lee Jong‐Sun Kang |
| author_facet | Hyebeen Kim Sung Chun Cho Hyeon‐Ju Jeong Hye‐Young Lee Myong‐Ho Jeong Jung‐Hoon Pyun Dongryeol Ryu MinSeok Kim Young‐Sam Lee Minseok S. Kim Sang Chul Park Yun‐Il Lee Jong‐Sun Kang |
| author_sort | Hyebeen Kim |
| collection | DOAJ |
| description | Abstract Background Muscle wasting, resulting from aging or pathological conditions, leads to reduced quality of life, increased morbidity, and increased mortality. Much research effort has been focused on the development of exercise mimetics to prevent muscle atrophy and weakness. In this study, we identified indoprofen from a screen for peroxisome proliferator‐activated receptor γ coactivator α (PGC‐1α) inducers and report its potential as a drug for muscle wasting. Methods The effects of indoprofen treatment on dexamethasone‐induced atrophy in mice and in 3‐phosphoinositide‐dependent protein kinase‐1 (PDK1)‐deleted C2C12 myotubes were evaluated by immunoblotting to determine the expression levels of myosin heavy chain and anabolic‐related and oxidative metabolism‐related proteins. Young, old, and disuse‐induced muscle atrophic mice were administered indoprofen (2 mg/kg body weight) by gavage. Body weight, muscle weight, grip strength, isometric force, and muscle histology were assessed. The expression levels of muscle mass‐related and function‐related proteins were analysed by immunoblotting or immunostaining. Results In young (3‐month‐old) and aged (22‐month‐old) mice, indoprofen treatment activated oxidative metabolism‐related enzymes and led to increased muscle mass. Mechanistic analysis using animal models and muscle cells revealed that indoprofen treatment induced the sequential activation of AKT/p70S6 kinase (S6K) and AMP‐activated protein kinase (AMPK), which in turn can augment protein synthesis and PGC‐1α induction, respectively. Structural prediction analysis identified PDK1 as a target of indoprofen and, indeed, short‐term treatment with indoprofen activated the PDK1/AKT/S6K pathway in muscle cells. Consistent with this finding, PDK1 inhibition abrogated indoprofen‐induced AKT/S6K activation and hypertrophic response. Conclusions Our findings demonstrate the effects of indoprofen in boosting skeletal muscle mass through the sequential activation of PDK1/AKT/S6K and AMPK/PGC‐1α. Taken together, our results suggest that indoprofen represents a potential drug to prevent muscle wasting and weakness related to aging or muscle diseases. |
| first_indexed | 2024-04-24T08:29:46Z |
| format | Article |
| id | doaj.art-13ad659c65f74560a49c27dd08c3a9c7 |
| institution | Directory Open Access Journal |
| issn | 2190-5991 2190-6009 |
| language | English |
| last_indexed | 2024-04-24T08:29:46Z |
| publishDate | 2020-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Cachexia, Sarcopenia and Muscle |
| spelling | doaj.art-13ad659c65f74560a49c27dd08c3a9c72024-04-16T20:22:11ZengWileyJournal of Cachexia, Sarcopenia and Muscle2190-59912190-60092020-08-011141070108810.1002/jcsm.12558Indoprofen prevents muscle wasting in aged mice through activation of PDK1/AKT pathwayHyebeen Kim0Sung Chun Cho1Hyeon‐Ju Jeong2Hye‐Young Lee3Myong‐Ho Jeong4Jung‐Hoon Pyun5Dongryeol Ryu6MinSeok Kim7Young‐Sam Lee8Minseok S. Kim9Sang Chul Park10Yun‐Il Lee11Jong‐Sun Kang12Department of Molecular Cell Biology, Single Cell Network Research Center Sungkyunkwan University Suwon South KoreaWell Aging Research Center, Division of Biotechnology Daegu Gyeongbuk Institute of Science and Technology (DGIST) Daegu South KoreaDepartment of Molecular Cell Biology, Single Cell Network Research Center Sungkyunkwan University Suwon South KoreaDepartment of Molecular Cell Biology, Single Cell Network Research Center Sungkyunkwan University Suwon South KoreaDepartment of Molecular Cell Biology, Single Cell Network Research Center Sungkyunkwan University Suwon South KoreaDepartment of Molecular Cell Biology, Single Cell Network Research Center Sungkyunkwan University Suwon South KoreaDepartment of Molecular Cell Biology, Single Cell Network Research Center Sungkyunkwan University Suwon South KoreaSchool of Undergraduate Studies Daegu Gyeongbuk Institute of Science and Technology (DGIST) Daegu South KoreaDepartment of New Biology Daegu Gyeongbuk Institute of Science and Technology (DGIST) Daegu South KoreaDepartment of New Biology Daegu Gyeongbuk Institute of Science and Technology (DGIST) Daegu South KoreaWell Aging Research Center, Division of Biotechnology Daegu Gyeongbuk Institute of Science and Technology (DGIST) Daegu South KoreaWell Aging Research Center, Division of Biotechnology Daegu Gyeongbuk Institute of Science and Technology (DGIST) Daegu South KoreaDepartment of Molecular Cell Biology, Single Cell Network Research Center Sungkyunkwan University Suwon South KoreaAbstract Background Muscle wasting, resulting from aging or pathological conditions, leads to reduced quality of life, increased morbidity, and increased mortality. Much research effort has been focused on the development of exercise mimetics to prevent muscle atrophy and weakness. In this study, we identified indoprofen from a screen for peroxisome proliferator‐activated receptor γ coactivator α (PGC‐1α) inducers and report its potential as a drug for muscle wasting. Methods The effects of indoprofen treatment on dexamethasone‐induced atrophy in mice and in 3‐phosphoinositide‐dependent protein kinase‐1 (PDK1)‐deleted C2C12 myotubes were evaluated by immunoblotting to determine the expression levels of myosin heavy chain and anabolic‐related and oxidative metabolism‐related proteins. Young, old, and disuse‐induced muscle atrophic mice were administered indoprofen (2 mg/kg body weight) by gavage. Body weight, muscle weight, grip strength, isometric force, and muscle histology were assessed. The expression levels of muscle mass‐related and function‐related proteins were analysed by immunoblotting or immunostaining. Results In young (3‐month‐old) and aged (22‐month‐old) mice, indoprofen treatment activated oxidative metabolism‐related enzymes and led to increased muscle mass. Mechanistic analysis using animal models and muscle cells revealed that indoprofen treatment induced the sequential activation of AKT/p70S6 kinase (S6K) and AMP‐activated protein kinase (AMPK), which in turn can augment protein synthesis and PGC‐1α induction, respectively. Structural prediction analysis identified PDK1 as a target of indoprofen and, indeed, short‐term treatment with indoprofen activated the PDK1/AKT/S6K pathway in muscle cells. Consistent with this finding, PDK1 inhibition abrogated indoprofen‐induced AKT/S6K activation and hypertrophic response. Conclusions Our findings demonstrate the effects of indoprofen in boosting skeletal muscle mass through the sequential activation of PDK1/AKT/S6K and AMPK/PGC‐1α. Taken together, our results suggest that indoprofen represents a potential drug to prevent muscle wasting and weakness related to aging or muscle diseases.https://doi.org/10.1002/jcsm.12558Exercise mimeticHypertrophic responseIndoprofenMuscle wastingMuscle weaknessPDK1 |
| spellingShingle | Hyebeen Kim Sung Chun Cho Hyeon‐Ju Jeong Hye‐Young Lee Myong‐Ho Jeong Jung‐Hoon Pyun Dongryeol Ryu MinSeok Kim Young‐Sam Lee Minseok S. Kim Sang Chul Park Yun‐Il Lee Jong‐Sun Kang Indoprofen prevents muscle wasting in aged mice through activation of PDK1/AKT pathway Journal of Cachexia, Sarcopenia and Muscle Exercise mimetic Hypertrophic response Indoprofen Muscle wasting Muscle weakness PDK1 |
| title | Indoprofen prevents muscle wasting in aged mice through activation of PDK1/AKT pathway |
| title_full | Indoprofen prevents muscle wasting in aged mice through activation of PDK1/AKT pathway |
| title_fullStr | Indoprofen prevents muscle wasting in aged mice through activation of PDK1/AKT pathway |
| title_full_unstemmed | Indoprofen prevents muscle wasting in aged mice through activation of PDK1/AKT pathway |
| title_short | Indoprofen prevents muscle wasting in aged mice through activation of PDK1/AKT pathway |
| title_sort | indoprofen prevents muscle wasting in aged mice through activation of pdk1 akt pathway |
| topic | Exercise mimetic Hypertrophic response Indoprofen Muscle wasting Muscle weakness PDK1 |
| url | https://doi.org/10.1002/jcsm.12558 |
| work_keys_str_mv | AT hyebeenkim indoprofenpreventsmusclewastinginagedmicethroughactivationofpdk1aktpathway AT sungchuncho indoprofenpreventsmusclewastinginagedmicethroughactivationofpdk1aktpathway AT hyeonjujeong indoprofenpreventsmusclewastinginagedmicethroughactivationofpdk1aktpathway AT hyeyounglee indoprofenpreventsmusclewastinginagedmicethroughactivationofpdk1aktpathway AT myonghojeong indoprofenpreventsmusclewastinginagedmicethroughactivationofpdk1aktpathway AT junghoonpyun indoprofenpreventsmusclewastinginagedmicethroughactivationofpdk1aktpathway AT dongryeolryu indoprofenpreventsmusclewastinginagedmicethroughactivationofpdk1aktpathway AT minseokkim indoprofenpreventsmusclewastinginagedmicethroughactivationofpdk1aktpathway AT youngsamlee indoprofenpreventsmusclewastinginagedmicethroughactivationofpdk1aktpathway AT minseokskim indoprofenpreventsmusclewastinginagedmicethroughactivationofpdk1aktpathway AT sangchulpark indoprofenpreventsmusclewastinginagedmicethroughactivationofpdk1aktpathway AT yunillee indoprofenpreventsmusclewastinginagedmicethroughactivationofpdk1aktpathway AT jongsunkang indoprofenpreventsmusclewastinginagedmicethroughactivationofpdk1aktpathway |