한빛사 논문
Hyebeen Kim1, Sung Chun Cho3,*, Hyeon-Ju Jeong1, Hye-Young Lee1, Myong-Ho Jeong1, Jung-Hoon Pyun1, Dongryeol Ryu1,2, MinSeok Kim4, Young-Sam Lee5, Minseok S. Kim5, Sang Chul Park3, Yun-Il Lee3,* & Jong-Sun Kang1,2,*
1 Department of Molecular Cell Biology, Single Cell Network Research Center, Sungkyunkwan University, Suwon, South Korea, 2 Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, South Korea, 3 Well Aging Research Center, Division of Biotechnology, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, South Korea, 4 School of Undergraduate Studies, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, South Korea, 5 Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, South Korea
*Correspondence to: Jong-Sun Kang, PhD, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, 2066, Seobu-Ro, Jangan-gu, Suwon, 16419, Korea.
Yun-Il Lee, PhD, Well Aging Research Center, Division of Biotechnology, Daegu Gyeongbuk Institute of Science and Technology (DGIST), 333 Techno Jungang-daero, Hyeonpung-myeon, Dalseong-gun, Daegu 42988, Korea.
Sung Chun Cho, PhD, Well Aging Research Center, Daegu Gyeongbuk Institute of Science and Technology (DGIST), 333 Techno Jungang-daero, Hyeonpung-myeon, Dalseonggun, Daegu 42988, Koreas.
Hyebeen Kim and Sung Chun Cho contributed equally to this work.
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.
Keywords Exercise mimetic; Hypertrophic response; Indoprofen; Muscle wasting; Muscle weakness; PDK1
논문정보
관련 링크
연구자 키워드
연구자 ID
관련분야 연구자보기
관련분야 논문보기
해당논문 저자보기