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J. Cachexia Sarcopenia Muscle, Dec 17 2024, | https://doi.org/10.1002/jcsm.13665
Lonafarnib Protects Against Muscle Atrophy Induced by Dexamethasone
Sanghoon Bae 1, Van-Hieu Mai 2, Seyoung Mun 3,4,5,6, Dalong Dong 1,7, Kyudong Han 3,4,5, Sunghyouk Park 2, Jung Keun Hyun 1,7,8,9
1Department of Nanobiomedical Science & BK21 NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, Korea
2NaturalProduct Research Institute, College of Pharmacy, Seoul National University, Seoul, Korea
3Department of Microbiology, College of Science & Technology,Dankook University, Cheonan, Korea
4Smart Animal Bio Institute, Dankook University, Cheonan, Korea
5Center for Bio-Medical Core Facility,Dankook University, Cheonan, Korea
6College of Science & Technology, Dankook University, Cheonan, Korea
7Institute of Tissue RegenerationEngineering (ITREN), Dankook University, Cheonan, Korea
8Department of Rehabilitation Medicine, College of Medicine, Dankook University,Cheonan, Korea
9Wiregene Co. Ltd., Chungju, Korea
Correspondence: Sunghyouk Park, Jung Keun Hyun
1Department of Nanobiomedical Science & BK21 NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, Korea
2NaturalProduct Research Institute, College of Pharmacy, Seoul National University, Seoul, Korea
3Department of Microbiology, College of Science & Technology,Dankook University, Cheonan, Korea
4Smart Animal Bio Institute, Dankook University, Cheonan, Korea
5Center for Bio-Medical Core Facility,Dankook University, Cheonan, Korea
6College of Science & Technology, Dankook University, Cheonan, Korea
7Institute of Tissue RegenerationEngineering (ITREN), Dankook University, Cheonan, Korea
8Department of Rehabilitation Medicine, College of Medicine, Dankook University,Cheonan, Korea
9Wiregene Co. Ltd., Chungju, Korea
Correspondence: Sunghyouk Park, Jung Keun Hyun
Abstract
Background
Muscle atrophy, including glucocorticoid-induced muscle wasting from treatments such as dexamethasone (DEX), results in significant reductions in muscle mass, strength and function. This study investigates the potential of lonafarnib, a farnesyltransferase inhibitor, to counteract DEX-induced muscle atrophy by targeting key signalling pathways.
Methods
We utilized in vitro models with C2C12 myotubes treated with DEX and in vivo models with Caenorhabditis elegans and DEX-treated Sprague–Dawley rats. Myotube morphology was assessed by measuring area, fusion index and diameter. Muscle function was evaluated by grip strength and compound muscle action potential (CMAP) in the gastrocnemius (GC) and tibialis anterior (TA) muscles. Molecular mechanisms were explored through RNA sequencing and Western blotting to assess changes in mitochondrial function and muscle signalling pathways.
Results
Lonafarnib (2 μM) significantly improved myotube area (1.49 ± 0.14 × 105 μm2 vs. 1.03 ± 0.49 × 105 μm2 in DEX, p < 0.05), fusion index (18.73 ± 1.23% vs. 13.3 ± 1.56% in DEX, p < 0.05) and myotube diameter (31.89 ± 0.89 μm vs. 21.56 ± 1.01 μm in DEX, p < 0.05) in C2C12 myotubes. In C. elegans, lonafarnib (100 μM) increased the pharyngeal pumping rate from 212 ± 7.21 contractions/min in controls to 308 ± 17.09 contractions/min at day 4 (p < 0.05), indicating enhanced neuromuscular function. In DEX-induced atrophic rats, lonafarnib improved maximal grip strength (DEX: 13.91 ± 0.78 N vs. 1 μM lonafarnib: 16.18 ± 0.84 N and 5 μM lonafarnib: 16.71 ± 0.83 N, p < 0.05), increased muscle weight in GC, and enhanced CMAP amplitudes in both GC and TA muscles. Western blot analysis showed that lonafarnib treatment upregulated UCP3 and ANGPTL4 and increased phosphorylation of mTOR and S6 ribosomal protein (p < 0.05), indicating enhanced mitochondrial function and protein synthesis. Knockdown models further demonstrated that lonafarnib could partially rescue muscle atrophy phenotypes, indicating its action through multiple molecular pathways.
Conclusions
Lonafarnib mitigates dexamethasone-induced muscle atrophy by enhancing mitochondrial function and activating anabolic pathways. These findings support further investigation of lonafarnib as a therapeutic agent for muscle atrophy in clinical settings.
Muscle atrophy, including glucocorticoid-induced muscle wasting from treatments such as dexamethasone (DEX), results in significant reductions in muscle mass, strength and function. This study investigates the potential of lonafarnib, a farnesyltransferase inhibitor, to counteract DEX-induced muscle atrophy by targeting key signalling pathways.
Methods
We utilized in vitro models with C2C12 myotubes treated with DEX and in vivo models with Caenorhabditis elegans and DEX-treated Sprague–Dawley rats. Myotube morphology was assessed by measuring area, fusion index and diameter. Muscle function was evaluated by grip strength and compound muscle action potential (CMAP) in the gastrocnemius (GC) and tibialis anterior (TA) muscles. Molecular mechanisms were explored through RNA sequencing and Western blotting to assess changes in mitochondrial function and muscle signalling pathways.
Results
Lonafarnib (2 μM) significantly improved myotube area (1.49 ± 0.14 × 105 μm2 vs. 1.03 ± 0.49 × 105 μm2 in DEX, p < 0.05), fusion index (18.73 ± 1.23% vs. 13.3 ± 1.56% in DEX, p < 0.05) and myotube diameter (31.89 ± 0.89 μm vs. 21.56 ± 1.01 μm in DEX, p < 0.05) in C2C12 myotubes. In C. elegans, lonafarnib (100 μM) increased the pharyngeal pumping rate from 212 ± 7.21 contractions/min in controls to 308 ± 17.09 contractions/min at day 4 (p < 0.05), indicating enhanced neuromuscular function. In DEX-induced atrophic rats, lonafarnib improved maximal grip strength (DEX: 13.91 ± 0.78 N vs. 1 μM lonafarnib: 16.18 ± 0.84 N and 5 μM lonafarnib: 16.71 ± 0.83 N, p < 0.05), increased muscle weight in GC, and enhanced CMAP amplitudes in both GC and TA muscles. Western blot analysis showed that lonafarnib treatment upregulated UCP3 and ANGPTL4 and increased phosphorylation of mTOR and S6 ribosomal protein (p < 0.05), indicating enhanced mitochondrial function and protein synthesis. Knockdown models further demonstrated that lonafarnib could partially rescue muscle atrophy phenotypes, indicating its action through multiple molecular pathways.
Conclusions
Lonafarnib mitigates dexamethasone-induced muscle atrophy by enhancing mitochondrial function and activating anabolic pathways. These findings support further investigation of lonafarnib as a therapeutic agent for muscle atrophy in clinical settings.
논문정보
- Research article
- 2024년 12월 (BRIC 등록일 2024-12-18)
- 국내 연구진
- 의약학 > 응용의학
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