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J. Cachexia Sarcopenia Muscle, Feb 2025, 16 (1) | https://doi.org/10.1002/jcsm.13704
Celecoxib Enhances Oxidative Muscle Fibre Formation and Improves Muscle Functions Through Prokr1 Activation in Mice
Jeong Hwan Park 1, Jongsoo Mok 1, Seoah Park 1, Dooho Kim 1, Min-Su Kang 1, Tae Sub Park 1,2, Joonghoon Park 1,2
1 Department of International Agricultural Technology, Graduate School of International Agricultural Technology, Seoul National University, Seoul, Republic of Korea
2 Institute of Green Bio Science and Technology, Seoul National University, Seoul, Republic of Korea
Correspondence: Joonghoon Park
1 Department of International Agricultural Technology, Graduate School of International Agricultural Technology, Seoul National University, Seoul, Republic of Korea
2 Institute of Green Bio Science and Technology, Seoul National University, Seoul, Republic of Korea
Correspondence: Joonghoon Park
Abstract
Background: Muscle diseases are serious challenges to human health. Prokineticin receptor 1 (PROKR1) has emerged as a potential target to improve muscle function through increasing oxidative muscle fibres, but there are no clinically applicable synthetic PROKR1 agonists.
Methods: Drugs with biological properties of prokineticin 2 (PK2) were discovered through connectivity map (CMap) analysis. Their effects on PROKR1 were evaluated using molecular docking, PROKR1 signalling and competitive binding assays. Pregnant dams were fed diets containing varying celecoxib concentrations (0, 500, 1000 and 1500 ppm) from gestation day 5 through weaning. Offspring were given high-fat diets (HFD) from weaning until 20 weeks old, and body composition, insulin resistance, energy expenditure, exercise performance and histological analysis of muscle tissues were evaluated.
Results: Celecoxib, with a connectivity score of 64.19 to PK2 and a docking score of -9.0 to PROKR1, selectively activated Gs signalling at 4 μM of EC50 and increased NR4A2 protein levels by 1.6-fold (p < 0.01) in PROKR1-overexpressing cells. It competitively inhibited PK2 binding to PROKR1 and reduced cAMP accumulation. In murine and human myotubes, celecoxib increased Prokr1 protein levels by 1.8-fold (p < 0.05), pCreb by 1.5-fold (p < 0.05) and Nr4a2 by 1.3-fold (p < 0.05). It also elevated Myh7 index by 2.2-fold (p < 0.0001), mitochondrial content by 1.6-fold (p < 0.001) and fatty acid oxidation (FAO) activity by 4.1-fold (p < 0.05). Offspring exposed to celecoxib during pre- and postnatal muscle development exhibited activated Prokr1 signalling, enhanced oxidative muscle fibre formation and improved muscle phenotype despite HFD. At weaning, both male and female offspring showed dose-dependent increases in lean mass (> 9.35%, p < 0.001) and grip strength (< 18.0%, p < 0.01). At 12 weeks old, mice displayed a dose-dependent decrease in weight loss (> 13.3%, p < 0.05), increased lean mass (> 16.2%, p < 0.05), improved insulin resistance (> 70.4%, p < 0.0001), energy expenditure (> 173%, p < 0.0001) and grip strength (> 23.5%, p < 0.001). Celecoxib also increased Myh7-positive muscle fibre composition (> 10.8%, p < 0.05) and mitochondrial mass (> 32.8%, p < 0.05) in the gastrocnemius and soleus muscles, accompanied by significant Prokr1 signalling activation. These effects persisted in both male and female mice at 20 weeks old.
Conclusions: Celecoxib shows promise as a PROKR1 agonist and clinically applicable exercise mimetic for the treatment of muscular disorders.
Methods: Drugs with biological properties of prokineticin 2 (PK2) were discovered through connectivity map (CMap) analysis. Their effects on PROKR1 were evaluated using molecular docking, PROKR1 signalling and competitive binding assays. Pregnant dams were fed diets containing varying celecoxib concentrations (0, 500, 1000 and 1500 ppm) from gestation day 5 through weaning. Offspring were given high-fat diets (HFD) from weaning until 20 weeks old, and body composition, insulin resistance, energy expenditure, exercise performance and histological analysis of muscle tissues were evaluated.
Results: Celecoxib, with a connectivity score of 64.19 to PK2 and a docking score of -9.0 to PROKR1, selectively activated Gs signalling at 4 μM of EC50 and increased NR4A2 protein levels by 1.6-fold (p < 0.01) in PROKR1-overexpressing cells. It competitively inhibited PK2 binding to PROKR1 and reduced cAMP accumulation. In murine and human myotubes, celecoxib increased Prokr1 protein levels by 1.8-fold (p < 0.05), pCreb by 1.5-fold (p < 0.05) and Nr4a2 by 1.3-fold (p < 0.05). It also elevated Myh7 index by 2.2-fold (p < 0.0001), mitochondrial content by 1.6-fold (p < 0.001) and fatty acid oxidation (FAO) activity by 4.1-fold (p < 0.05). Offspring exposed to celecoxib during pre- and postnatal muscle development exhibited activated Prokr1 signalling, enhanced oxidative muscle fibre formation and improved muscle phenotype despite HFD. At weaning, both male and female offspring showed dose-dependent increases in lean mass (> 9.35%, p < 0.001) and grip strength (< 18.0%, p < 0.01). At 12 weeks old, mice displayed a dose-dependent decrease in weight loss (> 13.3%, p < 0.05), increased lean mass (> 16.2%, p < 0.05), improved insulin resistance (> 70.4%, p < 0.0001), energy expenditure (> 173%, p < 0.0001) and grip strength (> 23.5%, p < 0.001). Celecoxib also increased Myh7-positive muscle fibre composition (> 10.8%, p < 0.05) and mitochondrial mass (> 32.8%, p < 0.05) in the gastrocnemius and soleus muscles, accompanied by significant Prokr1 signalling activation. These effects persisted in both male and female mice at 20 weeks old.
Conclusions: Celecoxib shows promise as a PROKR1 agonist and clinically applicable exercise mimetic for the treatment of muscular disorders.
논문정보
- Research article
- 2025년 02월 (BRIC 등록일 2025-02-03)
- 국내 연구진
- 생명과학 > 노화/암생물학
관련 보도자료
셀레콕시브의 Prokr1 활성화를 통한 산화 근섬유 형성 촉진 및 근육 기능 개선 효과
서울대학교 국제농업기술대학원 (경제동물과학 전공) 박중훈 교수 연구진은 PROKR1이 산화성 근섬유의 분화를 촉진하고 근육량 및 근력이 개선되는 효과를 입증한 후, PROKR1에 대한 저분자 작용제 연구를 통해 셀레콕시브를 발굴하였다. 임신 중 셀렉콕시브에 의해 PROKR1 활성 효과가 각인된 마우스는 출생 후 20주령까지 고지방식이 조건에서도 PROKR1 신호전달경로의 지속적인 활성을 통해 미토콘드리아가 풍부한 산화성 근섬유 증가와 이를 통한 에너지 소비량, 지방산 산화능의 증가, 인슐린 저항성 개선, 그리고 체지방량의 감소를 동반한 전신적인 대사능 향상을 유지하였다.
- Bio통신원
- 2025. 02. 07
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