Research on the role and mechanism of trimetazidine in ICU-acquired weakness_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

WANG Qin ^1,2 , LIN Ning ³ , WANG Jiayu ^1,2 , BAI Yujie ² , LI Mei ⁴ , SHI Peijie ^1,3 , LUO Shuhong ⁵ ,  FENG Jian ² ,  LI Fuxiang ^1,2

1. College of Medicine, Southwest Jiaotong University, Chengdu, Sichuan 610031, P. R. China;
2. Department of Intensive Care Medicine, General Hospital of Western Theater Command, Chengdu, Sichuan 610083, P. R. China;
3. Department of Nutrition, General Hospital of Western Theater Command, Chengdu, Sichuan 610083, P. R. China;
4. Department of Intensive Care Medicine, People’s Hospital of Dali Bai Autonomous Prefecture, Dali, Yunnan 671000, P. R. China;
5. Department of Respiratory and Critical Care Medicine, The First People’s Hospital of Shuangliu District, Chengdu, Sichuan 610200, P. R. China;

Corresponding author：

FENG Jian, Email: lfx98@163.com; LI Fuxiang, Email: ironvon@foxmail.com

Keywords：

Intensive care unit-acquired weakness; trimetazidine; sepsis; pyroptosis; cysteinyl aspartate specific proteinase 1; gasdermin D

DOI：

10.7507/1671-6205.202312046

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Objective To investigate the role and mechanisms of trimetazidine (TMZ) in intensive care unit-acquired weakness (ICU-AW). Methods Seventy wild-type male C57BL/6 mice were selected and the ICU-AW mouse model was constructed by intraperitoneal injection of different concentrations of lipopolysaccharide (LPS). The body weights, grip strengths, and 96-hour survival rates of each group were observed, and the optimal concentration of LPS and time of sampling were screened out, the mRNA and protein expression of the gastrocnemius muscle atrophic proteins Atrogin-1 and muscle-specific RING finger protein 1 (MuRF1) were further detected to verify the success of modelling, and LPS (12 mg/kg) was used as the subsequent modelling concentration according to the preliminary results. After successful modelling, another 70 mice were randomly divided into normal control group (Normal group), LPS solvent (Vehicle) group, LPS group, LPS+TMZ solvent group, LPS+TMZ group, LPS+TMZ+AC-YVAD-CMK (AC) solvent group, and LPS+TMZ+AC group, with 10 mice in each group. The Normal group did not have any intervention; the Vehicle group was injected intraperitoneally with an equal volume of saline with LPS; the remaining groups were injected intraperitoneally with LPS (12 mg/kg); after the completion of the LPS injection, the LPS+TMZ group, the LPS+TMZ+AC solvent group, and the LPS+TMZ+AC group were given TMZ (5 mg/kg) by gastric gavage once a day for 4 days. The LPS+TMZ solvent group was given TMZ equivalent saline gavage once a day for 4 days. The LPS+TMZ+AC group was injected intraperitoneally with the cysteinyl aspartate specific proteinase 1 (Caspase-1) inhibitor AC-YVAD-CMK (AC, 6.5 mg/kg) 1 h before LPS injection, and the LPS+TMZ+AC solvent group was injected with an equal amount of AC solvent phosphate buffer. At the end of TMZ treatment, body weight, grip strength, 96-hour survival rate, mRNA and protein expression of MuRF1, Atrogin-1, Caspase-1, and gasdermin D (GSDMD) in gastrocnemius muscle, as well as serum IL-1β and IL-18 concentrations in mice were detected in each group, and the gastrocnemius muscle was stained with HE to observe histopathological changes. Results Compared with the Normal group, mice in the LPS (12 mg/kg) and LPS (14 mg/kg) groups showed significant decreases in body weight and grasping strength and the weakening was most obvious at 3 - 5 d (P<0.05), but the survival rate of the LPS (12 mg/kg) group was higher than that of the LPS (14 mg/kg) group (P<0.05), the HE staining of gastrocnemius muscle showed that the mice in the LPS (12 mg/kg) group was significantly atrophied compared with that of the Normal group, and the gene and protein expression of MuRF1 and Atrogin-1 were significantly elevated (P<0.05), and the mice injected with LPS (12 mg/kg) for 4 days (96 h) were finally selected as the conditions for subsequent experimental modelling and sampling.The mRNA and protein expression of Caspase-1 and GSDMD in skeletal muscle was significantly higher in the LPS group compared with the Normal and Vehicle groups (P<0.01), and the concentrations of serum IL-1β and IL-18 were significantly higher(P<0.01). Mice in the TMZ group showed significant improvement in body weight, grip strength, survival rate, and degree of muscle atrophy compared with the LPS and TMZ solvent groups (P<0.05); gene and protein levels of MuRF1, Atrogin-1, Caspase-1, and GSDMD in the gastrocnemius muscle were significantly reduced (P<0.05); and levels of serum IL-1β and IL-18 were significantly reduced (P<0.05) ); the mice in the LPS+TMZ+AC group had significantly improved body weight, grip strength, survival rate, and muscle atrophy compared with the LPS+TMZ group and the LPS+TMZ+AC solvent group (P<0.05), and the gene and protein contents of MuRF1, Atrogin-1, Caspase-1, and GSDMD in the gastrocnemius muscle were reduced (P<0.05), and the serum IL-1β and IL -18 concentrations were reduced (P<0.05). Conclusion TMZ is able to exert a skeletal muscle protective effect by inhibiting Caspase-1/GSDMD-mediated pyroptosis, which is an important reference for the prevention and treatment of ICU-AW.

Citation： WANG Qin, LIN Ning, WANG Jiayu, BAI Yujie, LI Mei, SHI Peijie, LUO Shuhong, FENG Jian, LI Fuxiang. Research on the role and mechanism of trimetazidine in ICU-acquired weakness. Chinese Journal of Respiratory and Critical Care Medicine, 2024, 23(7): 478-487. doi: 10.7507/1671-6205.202312046 Copy

1.	Vanhorebeek I, Latronico N, Van den Berghe G. ICU-acquired weakness. Intensive Care Med, 2020, 46(4): 637-653.
2.	Mayer KP, Thompson ML, Montgomery AA, et al. Acute skeletal muscle wasting and dysfunction predict physical disability at hospital discharge in patients with critical illness. Crit Care, 2020, 24(1): 637.
3.	Fazzini B, Märkl T, Costas C, et al. The rate and assessment of muscle wasting during critical illness: a systematic review and meta-analysis. Crit Care, 2023, 27(1): 2.
4.	Chen J, Chen XY, Cong XX, et al. Cellular senescence implicated in sepsis-induced muscle weakness and ameliorated with metformin. Shock, 2023, 59(4): 646-656.
5.	Rocheteau P, Chatre L, Briand D, et al. Sepsis induces long-term metabolic and mitochondrial muscle stem cell dysfunction amenable by mesenchymal stem cell therapy. Nat Commun, 2015, 6: 10145.
6.	王银燕, 施荣华, 林志敏, 等. 慢性阻塞性肺疾病患者机械通气撤机前膈肌收缩功能的研究. 中国呼吸与危重监护杂志, 2019, 18(5): 423-426.
7.	Bonaldo P, Sandri M. Cellular and molecular mechanisms of muscle atrophy. Dis Model Mech, 2013, 6(1): 25-39.
8.	Stana F, Vujovic M, Mayaki D, et al. Differential regulation of the autophagy and proteasome pathways in skeletal muscles in sepsis. Crit Care Med, 2017, 45(9): e971-e979.
9.	Vasudevan SO, Behl B, Rathinam VA. Pyroptosis-induced inflammation and tissue damage. Semin Immunol, 2023, 69: 101781.
10.	Chen X, Lin S, Dai S, et al. Trimetazidine affects pyroptosis by targeting GSDMD in myocardial ischemia/reperfusion injury. Inflamm Res, 2022, 71(2): 227-241.
11.	Wang L, Jiao XF, Wu C, et al. Trimetazidine attenuates dexamethasone-induced muscle atrophy via inhibiting NLRP3/GSDMD pathway-mediated pyroptosis. Cell Death Discov, 2021, 7(1): 251.
12.	Zhang J, Wang M, Hu X, et al. Electroacupuncture-driven endogenous circulating serum exosomes as a potential therapeutic strategy for sepsis. Chin Med, 2023, 18(1): 106.
13.	Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm, 2016, 7(2): 27-31.
14.	Lin JQ, Wang JX, Yu S, et al. Newly discovered molecules associated with trimetazidine on improvement of skeletal muscle function in aging: evidence from myoblasts and mice. Exp Gerontol, 2022, 161: 111733.
15.	Wu DD, Pan PH, Liu B, et al. Inhibition of alveolar macrophage pyroptosis reduces lipopolysaccharide-induced acute lung injury in mice. Chin Med J (Engl), 2015, 128(19): 2638-45.
16.	Witteveen E, Hoogland IC, Wieske L, et al. Assessment of intensive care unit-acquired weakness in young and old mice: an E. coli septic peritonitis model. Muscle Nerve. 2016, 53(1): 127-33.
17.	Stevens RD, Marshall SA, Cornblath DR, et al. A framework for diagnosing and classifying intensive care unit-acquired weakness. Crit Care Med, 2009, 37(10 Suppl): S299-S308.
18.	Latronico N, Bolton CF. Critical illness polyneuropathy and myopathy: a major cause of muscle weakness and paralysis. Lancet Neurol, 2011, 10(10): 931-941.
19.	Wang W, Xu C, Ma X, et al. Intensive care unit-acquired weakness: a review of recent progress with a look toward the future. Front Med (Lausanne), 2020, 7: 559789.
20.	卢娇, 梁国鹏, 王波, 等. 重症加强治疗病房有创机械通气患者早期肺康复研究进展. 中国呼吸与危重监护杂志, 2021, 20(11): 831-836.
21.	Chen J, Huang M. Intensive care unit-acquired weakness: recent insights. J Intensive Med, 2023, 4(1): 73-80.
22.	Zou W, Liu F, Li J, et al. Current status for animal models of intensive care unit acquired muscle weakness. Chinese, 2018, 43(6): 691-696.
23.	Li S, Wu Y, Yang D, et al. Gasdermin D in peripheral myeloid cells drives neuroinflammation in experimental autoimmune encephalomyelitis. J Exp Med, 2019, 216(11): 2562-2581.
24.	Xiao J, Wang C, Yao JC, et al. Gasdermin D mediates the pathogenesis of neonatal-onset multisystem inflammatory disease in mice. PLoS Biol, 2018, 16(11): e3000047.
25.	Chhetri JK, Fougère B, Rolland Y, et al. Chronic inflammation and sarcopenia: a regenerative cell therapy perspective. Exp Gerontol, 2018, 103: 115-123.
26.	Shi J, Zhao Y, Shao F, et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature, 2015, 526(7575): 660-665.
27.	Song M, Chen FF, Li YH, et al. Trimetazidine restores the positive adaptation to exercise training by mitigating statin-induced skeletal muscle injury. J CACHEXIA SARCOPENI, 2018, 9(1): 106-118.

1. Vanhorebeek I, Latronico N, Van den Berghe G. ICU-acquired weakness. Intensive Care Med, 2020, 46(4): 637-653.
2. Mayer KP, Thompson ML, Montgomery AA, et al. Acute skeletal muscle wasting and dysfunction predict physical disability at hospital discharge in patients with critical illness. Crit Care, 2020, 24(1): 637.
3. Fazzini B, Märkl T, Costas C, et al. The rate and assessment of muscle wasting during critical illness: a systematic review and meta-analysis. Crit Care, 2023, 27(1): 2.
4. Chen J, Chen XY, Cong XX, et al. Cellular senescence implicated in sepsis-induced muscle weakness and ameliorated with metformin. Shock, 2023, 59(4): 646-656.
5. Rocheteau P, Chatre L, Briand D, et al. Sepsis induces long-term metabolic and mitochondrial muscle stem cell dysfunction amenable by mesenchymal stem cell therapy. Nat Commun, 2015, 6: 10145.
6. 王银燕, 施荣华, 林志敏, 等. 慢性阻塞性肺疾病患者机械通气撤机前膈肌收缩功能的研究. 中国呼吸与危重监护杂志, 2019, 18(5): 423-426.
7. Bonaldo P, Sandri M. Cellular and molecular mechanisms of muscle atrophy. Dis Model Mech, 2013, 6(1): 25-39.
8. Stana F, Vujovic M, Mayaki D, et al. Differential regulation of the autophagy and proteasome pathways in skeletal muscles in sepsis. Crit Care Med, 2017, 45(9): e971-e979.
9. Vasudevan SO, Behl B, Rathinam VA. Pyroptosis-induced inflammation and tissue damage. Semin Immunol, 2023, 69: 101781.
10. Chen X, Lin S, Dai S, et al. Trimetazidine affects pyroptosis by targeting GSDMD in myocardial ischemia/reperfusion injury. Inflamm Res, 2022, 71(2): 227-241.
11. Wang L, Jiao XF, Wu C, et al. Trimetazidine attenuates dexamethasone-induced muscle atrophy via inhibiting NLRP3/GSDMD pathway-mediated pyroptosis. Cell Death Discov, 2021, 7(1): 251.
12. Zhang J, Wang M, Hu X, et al. Electroacupuncture-driven endogenous circulating serum exosomes as a potential therapeutic strategy for sepsis. Chin Med, 2023, 18(1): 106.
13. Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm, 2016, 7(2): 27-31.
14. Lin JQ, Wang JX, Yu S, et al. Newly discovered molecules associated with trimetazidine on improvement of skeletal muscle function in aging: evidence from myoblasts and mice. Exp Gerontol, 2022, 161: 111733.
15. Wu DD, Pan PH, Liu B, et al. Inhibition of alveolar macrophage pyroptosis reduces lipopolysaccharide-induced acute lung injury in mice. Chin Med J (Engl), 2015, 128(19): 2638-45.
16. Witteveen E, Hoogland IC, Wieske L, et al. Assessment of intensive care unit-acquired weakness in young and old mice: an E. coli septic peritonitis model. Muscle Nerve. 2016, 53(1): 127-33.
17. Stevens RD, Marshall SA, Cornblath DR, et al. A framework for diagnosing and classifying intensive care unit-acquired weakness. Crit Care Med, 2009, 37(10 Suppl): S299-S308.
18. Latronico N, Bolton CF. Critical illness polyneuropathy and myopathy: a major cause of muscle weakness and paralysis. Lancet Neurol, 2011, 10(10): 931-941.
19. Wang W, Xu C, Ma X, et al. Intensive care unit-acquired weakness: a review of recent progress with a look toward the future. Front Med (Lausanne), 2020, 7: 559789.
20. 卢娇, 梁国鹏, 王波, 等. 重症加强治疗病房有创机械通气患者早期肺康复研究进展. 中国呼吸与危重监护杂志, 2021, 20(11): 831-836.
21. Chen J, Huang M. Intensive care unit-acquired weakness: recent insights. J Intensive Med, 2023, 4(1): 73-80.
22. Zou W, Liu F, Li J, et al. Current status for animal models of intensive care unit acquired muscle weakness. Chinese, 2018, 43(6): 691-696.
23. Li S, Wu Y, Yang D, et al. Gasdermin D in peripheral myeloid cells drives neuroinflammation in experimental autoimmune encephalomyelitis. J Exp Med, 2019, 216(11): 2562-2581.
24. Xiao J, Wang C, Yao JC, et al. Gasdermin D mediates the pathogenesis of neonatal-onset multisystem inflammatory disease in mice. PLoS Biol, 2018, 16(11): e3000047.
25. Chhetri JK, Fougère B, Rolland Y, et al. Chronic inflammation and sarcopenia: a regenerative cell therapy perspective. Exp Gerontol, 2018, 103: 115-123.
26. Shi J, Zhao Y, Shao F, et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature, 2015, 526(7575): 660-665.
27. Song M, Chen FF, Li YH, et al. Trimetazidine restores the positive adaptation to exercise training by mitigating statin-induced skeletal muscle injury. J CACHEXIA SARCOPENI, 2018, 9(1): 106-118.

Chinese Journal of Respiratory and Critical Care Medicine

Research on the role and mechanism of trimetazidine in ICU-acquired weakness

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