Kun-Chang Wu1,2, Po-Chen Chu3, Yu-Jung Cheng4,5, Chia-Ing Li6,7, Jingkui Tian8,9, Hsing-Yu Wu10, Szu-Hsien Wu1,11, Yi-Chun Lai2, Hsiang-Han Kao12, Ao-Lin Hsu2,13,14, Hsiang-Wen Lin1,15,16, Chih-Hsueh Lin6,17. 1. School of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan. 2. Research Center for Healthy Aging, China Medical University, Taichung, Taiwan. 3. Department of Cosmeceutics and Graduate Institute of Cosmeceutics, China Medical University, Taichung, Taiwan. 4. Department of Physical Therapy and Graduate Institute of Rehabilitation Science, China Medical University, Taichung, Taiwan. 5. Department of Rehabilitation, China Medical University Hospital, Taichung, Taiwan. 6. School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan. 7. Department of Medical Research, China Medical University Hospital, Taichung, Taiwan. 8. Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China. 9. College of Biomedical Engineering & Instrument Science, Zhejiang University, Hangzhou, China. 10. Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan. 11. Institute of New Drug Development, China Medical University, Taichung, Taiwan. 12. Department of Family Medicine, China Medical University Hospital, Taichung, Taiwan. 13. PhD Program for Aging, China Medical University, Taichung, Taiwan. 14. Department of Internal Medicine, Division of Geriatrics & Palliative Medicine, University of Michigan Medical School, Ann Arbor, MI, USA. 15. Department of Pharmacy, China Medical University Hospital, Taichung, Taiwan. 16. Department of Pharmacy System, Outcomes and Policy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA. 17. Department of Geriatric Medicine, China Medical University Hospital, Taichung, Taiwan.
Abstract
BACKGROUND: Despite recent advances in understanding the pathophysiology of cancer cachexia, prevention/treatment of this debilitating disease remains an unmet medical need. METHODS: We developed an integrated, multi-tiered strategy involving both in vitro and in vivo muscle atrophy platforms to identify traditional Chinese medicine (TCM)-based anti-cachectic agents. In the initial screening, we used inflammatory cytokine-induced atrophy of C2C12 myotubes as a phenotypic screening platform to assess the protective effects of TCMs. The selected TCMs were then evaluated for their abilities to protect Caenorhabditis elegans from age-related reduction of mobility and contractility, followed by the C-26 colon adenocarcinoma mouse model of cachexia to confirm the anti-muscle atrophy effects (body/skeletal muscle weights, fibre size distribution, grip strengths, and serum IL-6). Transcriptome analysis, quantitative real-time polymerase chain reaction, and immunoblotting were performed to gain understanding of the potential mechanism(s) by which effective TCM protected against C26 tumour-induced muscle atrophy. RESULTS: Of 29 widely used TCMs, Dioscorea radix (DR) and Mu Dan Pi (MDP) showed a complete protection (all P values, 0.0002) vis-à-vis C26 conditioned medium control in the myotube atrophy platform. MDP exhibited a unique ability to ameliorate age-associated decreases in worm mobility, accompanied by improved total body contractions, relative to control (P < 0.0001 and <0.01, respectively), which, however, was not noted with DR. This differential in vivo protective effect between MDP and DR was also confirmed in the C-26 mouse model. MDP at 1000 mg/kg (MDP-H) was effective in protecting body weight loss (P < 0.05) in C-26 tumour-bearing mice without changing food or water intake, accompanied by the restoration of the fibre size distribution of hindleg skeletal muscles (P < 0.0001) and the forelimb grip strength (P < 0.05). MDP-treated C-26-tumour-bearing mice were alert, showed normal posture and better body conditions, and exhibited lower serum IL-6 levels (P = 0.06) relative to vehicle control. This decreased serum IL-6 was associated with the in vitro suppressive effect of MDP (25 and 50 μg/mL) on IL-6 secretion into culture medium by C26 cells. RNA-seq analysis, followed by quantitative real-time polymerase chain reaction and/or immunoblotting, shows that MDP's anti-cachectic effect was attributable to its ability to reverse the C-26 tumour-induced re-programming of muscle homoeostasis-associated gene expression, including that of two cachexia drivers (MuRF1 and Atrogin-1), in skeletal muscles. CONCLUSIONS: All these findings suggest the translational potential of MDP to foster new strategies for the prevention and/or treatment of cachexia. The protective effect of MDP on other types of muscle atrophy such as sarcopenia might warrant investigations.
BACKGROUND: Despite recent advances in understanding the pathophysiology of cancer cachexia, prevention/treatment of this debilitating disease remains an unmet medical need. METHODS: We developed an integrated, multi-tiered strategy involving both in vitro and in vivo muscle atrophy platforms to identify traditional Chinese medicine (TCM)-based anti-cachectic agents. In the initial screening, we used inflammatory cytokine-induced atrophy of C2C12 myotubes as a phenotypic screening platform to assess the protective effects of TCMs. The selected TCMs were then evaluated for their abilities to protect Caenorhabditis elegans from age-related reduction of mobility and contractility, followed by the C-26 colon adenocarcinoma mouse model of cachexia to confirm the anti-muscle atrophy effects (body/skeletal muscle weights, fibre size distribution, grip strengths, and serum IL-6). Transcriptome analysis, quantitative real-time polymerase chain reaction, and immunoblotting were performed to gain understanding of the potential mechanism(s) by which effective TCM protected against C26 tumour-induced muscle atrophy. RESULTS: Of 29 widely used TCMs, Dioscorea radix (DR) and Mu Dan Pi (MDP) showed a complete protection (all P values, 0.0002) vis-à-vis C26 conditioned medium control in the myotube atrophy platform. MDP exhibited a unique ability to ameliorate age-associated decreases in worm mobility, accompanied by improved total body contractions, relative to control (P < 0.0001 and <0.01, respectively), which, however, was not noted with DR. This differential in vivo protective effect between MDP and DR was also confirmed in the C-26 mouse model. MDP at 1000 mg/kg (MDP-H) was effective in protecting body weight loss (P < 0.05) in C-26 tumour-bearing mice without changing food or water intake, accompanied by the restoration of the fibre size distribution of hindleg skeletal muscles (P < 0.0001) and the forelimb grip strength (P < 0.05). MDP-treated C-26-tumour-bearing mice were alert, showed normal posture and better body conditions, and exhibited lower serum IL-6 levels (P = 0.06) relative to vehicle control. This decreased serum IL-6 was associated with the in vitro suppressive effect of MDP (25 and 50 μg/mL) on IL-6 secretion into culture medium by C26 cells. RNA-seq analysis, followed by quantitative real-time polymerase chain reaction and/or immunoblotting, shows that MDP's anti-cachectic effect was attributable to its ability to reverse the C-26 tumour-induced re-programming of muscle homoeostasis-associated gene expression, including that of two cachexia drivers (MuRF1 and Atrogin-1), in skeletal muscles. CONCLUSIONS: All these findings suggest the translational potential of MDP to foster new strategies for the prevention and/or treatment of cachexia. The protective effect of MDP on other types of muscle atrophy such as sarcopenia might warrant investigations.
Authors: Wei Li; Jennifer S Moylan; Melissa A Chambers; Jeffrey Smith; Michael B Reid Journal: Am J Physiol Cell Physiol Date: 2009-07-22 Impact factor: 4.249
Authors: Erin E Talbert; Maria C Cuitiño; Katherine J Ladner; Priyani V Rajasekerea; Melissa Siebert; Reena Shakya; Gustavo W Leone; Michael C Ostrowski; Brian Paleo; Noah Weisleder; Peter J Reiser; Amy Webb; Cynthia D Timmers; Daniel S Eiferman; David C Evans; Mary E Dillhoff; Carl R Schmidt; Denis C Guttridge Journal: Cell Rep Date: 2019-08-06 Impact factor: 9.423