The Role And Mechanism Of Adiponectin And Its Receptor AdipoR1 In Cancer Cachexia And Sarcopenia

Part 1:Adiponectin levels and risk of cancer cachexia: a systematic review and meta-analysisBackground: Studies have reported that adiponectin is involved in the development of cancer cachexia.However,the results are inconsistent.The purpose of the study was to confirm and clarify this association through a meta-analysis.Methods: Eligible studies were identified by a search in Pub Med,Web of science and EMBASE up to October 2018.The pooled standard mean differences(SMD)and 95% confidence intervals(CI)were examined through fixed-effects or random-effects models.Subgroup analysis,meta-regression and sensitivity analysis were conducted to assessed the heterogeneity.Publication bias was estimated by Begg`s test,Egger`s test and a trim and fill analysis.For statistical procedures,we used Stata Software,version 12.0(Stata Corp.,College Station,TX,USA).Results: A total of 10 studies containing 526 cancer patients published between 2006 and August 2017 were included in this meta-analysis.Cancer patients with cachexia had higher adiponectin levels as compared with those without cachexia(summary SMD = 0.415;95% CI = 0.100 – 0.731;P = 0.010;I2 = 65.0%).In subgroup analysis of cancer type,this difference was also significant in mixed cancer types(SMD = 0.900;95% CI = 0.556 – 1.244;P < 0.001)and lung cancer(SMD = 0.375;95% CI =-0.170 – 0.733;P = 0.040),but not in digestive system cancer.Conclusion: The current meta-analysis suggested that higher adiponectin level was positively associated with cachexia risk among cancer patients.Adiponectin has the potential to be a useful biomarker of cancer cachexia.Part 2:Level of adiponectin and biochemical parameters among cancer patients with sarcopeniaBackground: As the main manifestation of cachexia,sarcopenia has got increasing attention recent years.While the biomarker for diagnosis of sarcopenia among cancer patients is lacking.Researches have demonstrated that the level of adiponectin among cancer patients with cachexia is elevated,our study was aimed to investigate the plasma adiponectin concentration of cancer patients suffered with sarcopenia.Methods: A total of 185 cancer patients from Cancer Center of Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology were included in this cross-sectional study between May 2018 and June 2018.Serum level of adiponectin was tested by ELISA.Patients were divided into non-sarcopenia and sarcopenia based on the skeletal muscle index,SMI(<55 cm2/m2 for male,< 39 cm2/m2 for female).Blood concentrations of adiponectin,hemoglobin,albumin,creatine kinase,cholinesterase,creatinine and uric acid among sarcopenia patients were compared with non-sarcopenia patients.Associations between these biomarkers with SMI,handgrap strength and SARC-F score(to score muscle function)were evaluated.In addition,patients were divided into nonsarcopenia,pre-sarcopenia,sarcopenia and severe sarcopenia groups based on SMI,handgrip strength and SARC-F score to find further differences of adiponectin level between these groups.Results: Cancer patients with sarcopenia had significantly increased level of adiponectin compared to those without sarcopenia(7067.33 ng/ml > 5522.62 ng/ml,P = 0.008).Adiponectin level was negatively correlated with SMI(r =-0.222;P = 0.002)and positively with sarcopenia stage(r = 0.177,P = 0.016).Patients with sarcopenia had decreased blood level of albumin and cholinesterase,but elevated level of creatinine.Hemoglobin,albumin and creatinine concentrations were all associated with SMI of cancer patients.Conclusion: This study has evaluated the association between adiponectin level and sarcopenia comprehensively.The results demonstrated that cancer patients with sarcopenia had increased level of adiponectin which was also positively related to sarcopenia stage.As a conclusion,adiponectin may be a potential biomarker for sarcopenia among cancer patients.Blood biochemical parameters may also be good references during diagnosis and treatment of sarcopenia for cancer patients.Part 3:Tumor promotes loss of skeletal muscle via inhibiting the expression of AdipoR1Background: Sarcopenia has serious effects on quality of life and leads to poor prognosis among cancer patients.While the mechanisms of cancer related sarcopenia remain unclear,and associated articles are deficient.Our previous studies revealed that adiponectin was closely correlated with both cachexia and sarcopenia of cancer patients,especially with skeletal muscle mass.Therefore,we conducted experiments in vitro and in vivo to explore the potential role of adiponectin in process of cancer related sarcopenia.Methods: LLC cell line was cultured with serum-free medium for 12 hours.Tumor conditioned medium(CM)consisted of LLC supernatant and 2% horse serum.C2C12 myoblast was treated with CM.The proliferation was determined by CCK8 assay.The expression of AdipoR1,Mu RF1(Muscle-specific Ring Finger protein 1),Atrogin-1,and the activation of p38 MAPK,Akt,ERK were tested by Western blot.The expression of Myosin heavy chains(My HC)was tested by immunofluorescence.C2C12 cells were treated with adiponectin receptor agonist(Adipo R-A)or p38 MAPK inhibitor(SB 203580)combined with CM.Male mice were divided into three groups.Ctrl group did not receive any inoculation or treatment.TB group(Tumor bearing group)were inoculated with LLC and treated with normal saline for 20 days.TB+Adipo R-A group were inoculated with LLC and treated with Adipo R-A for 20 days.Body weight and tumor free body weight were recorded.The weight of gastrocnemius muscle was assessed.The cross section area of muscle fibers were calculated.Results: LLC conditioned medium inhibited the proliferation and differentiation of C2C12,and the expression of AdipoR1,while promoted the expression of Atrogin-1 and Mu RF1, and the activation of p38 MAPK.Adipo R-A alleviated the inhibition of differentiation from CM,but not proliferation.In addition,Adipo R-A reduced the expression of Atrogin-1 and Mu RF1,and the activation of p38 MAPK in C2C12.p38 MAPK inhibitor also reduced the expression of Atrogin-1 and Mu RF1.Tumor bearing mice treated with Adipo R-A had increased tumor free weight and gastrocnemius muscle weight,and elevated cross section area of gastrocnemius muscle fibers compared with tumor bearing group.Conclusions: Tumor promoted the expression of Atrogin-1 and Mu RF1,via reduced expression of Adpio R1 and elevated activation of p38 MAPK in C2C12,ultimately lead to the inhibition of skeletal muscle differentiation and sarcopenia.