Article first published online: 18 November 2018
Stephan von Haehling, Stefan D. Anker
von Haehling, S., and Anker, S. D. (2018) Once I get on a puzzle, I can't get off: Cachexia and wasting in 2018. Journal of Cachexia, Sarcopenia and Muscle, 9: 1021–1022. https://doi.org/10.1002/jcsm.12366.
Article first published online: 11 October 2018
Peter E. Penson, G. B. John Mancini, Peter P. Toth, Seth S. Martin, Gerald F. Watts, Amirhossein Sahebkar, Dimitri P. Mikhailidis, Maciej Banach on behalf of Lipid and Blood Pressure Meta‐Analysis Collaboration (LBPMC) Group & International Lipid Expert Panel (ILEP)
Introducing the ‘Drucebo’ effect in statin therapy: a systematic review of studies comparing reported rates of statin‐associated muscle symptoms, under blinded and open‐label conditions
The ‘placebo effect’ and ‘nocebo effect’ are phenomena whereby beneficial (placebo) or adverse (nocebo) effects result from the expectation that an inert substance will relieve or cause a particular symptom. These terms are often inappropriately applied to effects experienced on drug therapy. Quantifying the magnitude of placebo and nocebo effects in clinical trials is problematic because it requires a ‘no treatment’ arm. To overcome the difficulties associated with measuring the nocebo effect, and the fact that its definition refers to inert compounds, rather than drugs, we introduce the concept of ‘drucebo’ (a combination of DRUg and plaCEBO or noCEBO) to relate to beneficial or adverse effects of a drug, which result from expectation and are not pharmacologically caused by the drug. As an initial application of the concept, we have estimated the contribution of the drucebo effect to statin discontinuation and statin‐induced muscle symptoms by performing a systematic review of randomized controlled trial of statin therapy.
This preferred reporting items for systematic reviews and meta‐analysis‐compliant systematic review was prospectively registered in PROSPERO (CRD42017082700). We searched PubMed and Cochrane Central from inception until 3 January 2018 using a search strategy designed to detect studies including the concepts (Statins AND Placebo AND muscle pain). We included studies that allowed us to quantify the drucebo effect for adverse muscle symptoms of statins by (i) comparing reported rates of muscle symptoms in blinded and unblinded phases of randomized controlled trials and (ii) comparing rates of muscle symptoms at baseline and during blinded therapy in trials that included patients with objectively confirmed statin intolerance at baseline. Extraction was performed by two researchers with disagreements settled by a third reviewer.
Five studies allowed the estimation of the drucebo effect. All trials demonstrated an excess of side effects under open‐label conditions. The contribution of the drucebo effect to statin‐associated muscle pain ranged between 38% and 78%. The heterogeneity of study methods, outcomes, and reporting did not allow for quantitative synthesis (meta‐analysis) of the results.
The drucebo effect may be useful in evaluating the safety and efficacy of medicines. Diagnosis of the drucebo effect in patients presenting with statin intolerance will allow restoration of life‐prolonging lipid‐lowering therapy. Our study was limited by heterogeneity of included studies and lack of access to individual patient data. Further studies are necessary to better understand risk factors for and clinical management of the drucebo effect.
Penson, P. E., Mancini, G. B. J., Toth, P. P., Martin, S. S., Watts, G. F., Sahebkar, A., Mikhailidis, D. P., Banach, M., and on behalf of Lipid and Blood Pressure Meta‐Analysis Collaboration (LBPMC) Group & International Lipid Expert Panel (ILEP) (2018) Introducing the ‘Drucebo’ effect in statin therapy: a systematic review of studies comparing reported rates of statin‐associated muscle symptoms, under blinded and open‐label conditions. Journal of Cachexia, Sarcopenia and Muscle, 9: 1023–1033. https://doi.org/10.1002/jcsm.12344.
Article first published online: 6 August 2018
Jun‐Il Yoo, Mi‐Ji Kim, Jae‐Bum Na, Yun‐Hong Chun, Young‐Jin Park, Yongwhi Park, Young‐Sool Hah, Yong‐Chan Ha, Ki Soo Park
Relationship between endothelial function and skeletal muscle strength in community dwelling elderly women
The aim of this study is to determine whether there is correlation between endothelial function and skeletal muscle function measured by hand grip strength in elderly women.
This cross‐sectional study used data of NAMGARAM‐2 cohort. The NAMGARAM‐2 cohort consisted of a group of people living in three rural communities. They were enrolled for studies on activity limitation due to age‐related musculoskeletal disorders including knee osteoarthritis, osteoporosis, and sarcopenia. They were residents aged 40 years or older. They agreed to participate in this cohort from March 2016 to May 2017. Peripheral endothelial function was assessed by reactive hyperaemia‐peripheral arterial tonometry using EndoPAT2000 system. Hand grip strength was measured using a digital hand dynamometer.
Endothelial function index assessed by EndoPAT was worse in the low grip strength group than that in the normal group of elderly women (1.54 ± 0.51 in the low grip strength group vs. 1.77 ± 0.67 in the normal group, P = 0.003). There was a positive correlation between hand grip strength and endothelial function (r = 0.176, P = 0.007). On stepwise multivariate analysis, endothelial dysfunction (reactive hyperaemia‐peripheral arterial tonometry index < 1.67) significantly increased the risk of low hand grip strength (odds ratio = 2.019; 95% confidence interval = 1.107–3.682; P = 0.022).
Endothelial function and skeletal muscle strength had a significant correlation in elderly women, providing additional support for the relevant role of vascular system in sarcopenia.
Yoo, J.‐I., Kim, M.‐J., Na, J.‐B., Chun, Y.‐H., Park, Y.‐J., Park, Y., Hah, Y.‐S., Ha, Y.‐C., and Park, K. S. (2018) Relationship between endothelial function and skeletal muscle strength in community dwelling elderly women. Journal of Cachexia, Sarcopenia and Muscle, 9: 1034–1041. https://doi.org/10.1002/jcsm.12340.
Article first published online: 19 October 2018
Matthew F. Jacques, Gladys L. Onambele-Pearson, Neil D. Reeves, Georgina K. Stebbings, Jonathon Smith, Christopher I. Morse
Relationships between muscle size, strength, and physical activity in adults with muscular dystrophy
Muscular dystrophy (MD) is characterized by progressive muscle wasting and weakness, yet few comparisons to non-MD controls (CTRL) of muscle strength and size in this adult population exist. Physical activity (PA) is promoted to maintain health and muscle strength within MD; however, PA reporting in adults with MD is limited to recall data, and its impact on muscle strength is seldom explored.
This study included 76 participants: 16 non-MD (CTRL, mean age 35.4), 15 Duchenne MD (DMD, mean age 24.2), 18 Becker's MD (BMD, mean age 42.4), 13 limb-girdle MD (LGMD, mean age 43.1), and 14 facioscapulohumeral MD (mean age 47.7). Body fat (%) and lean body mass (LBM) were measured using bioelectrical-impedance. Gastrocnemius medialis (GM) anatomical cross-sectional area (ACSA) was determined using B-mode ultrasound. Isometric maximal voluntary contraction (MVC) was assessed during plantar flexion (PFMVC) and knee extension (KEMVC). PA was measured for seven continuous days using triaxial accelerometry and was expressed as daily average minutes being physically active (TPAmins) or average daily percentage of waking hours being sedentary (sedentary behaviour). Additionally, 10 m walk time was assessed.
Muscular dystrophy groups had 34–46% higher body fat (%) than CTRL. DMD showed differences in LBM with 21–28% less LBM than all other groups. PFMVC and KEMVC were 36–75% and 24–92% lower, respectively, in MD groups than CTRL. GM ACSA was 47% and 39% larger in BMD and LGMD, respectively, compared with CTRL. PFMVC was associated with GM ACSA in DMD (P = 0.026, R = 0.429) and CTRL (P = 0.015, R = 0.553). MD groups were 14–38% more sedentary than CTRL groups, while DMD were more sedentary than BMD (14%), LGMD (8%), and facioscapulohumeral MD (14%). Sedentary behaviour was associated with LBM in DMD participants (P = 0.021, R = -0.446). TPAmins was associated with KEMVC (P = 0.020, R = 0.540) in BMD participants, while TPAmins was also the best predictor of 10 m walk time (P < 0.001, R2 = 0.540) in ambulant MD, revealed by multiple linear regression.
Quantified muscle weakness and impaired 10 m walking time is reported in adults with MD. Muscle weakness and 10 m walk time were associated with lower levels of TPA in adults with MD. Higher levels of sedentary behaviour were associated with reduced LBM in DMD. These findings suggest a need for investigations into patterns of PA behaviour, and relevant interventions to reduce sedentary behaviour and encourage PA in adults with MD regardless of impairment severity.
Jacques, M. F., Onambele‐Pearson, G. L., Reeves, N. D., Stebbings, G. K., Smith, J., and Morse, C. I. (2018) Relationships between muscle size, strength, and physical activity in adults with muscular dystrophy. Journal of Cachexia, Sarcopenia and Muscle, 9: 1042–1052. https://doi.org/10.1002/jcsm.12347.
Article first published online: 29 September 2018
Maryam Ebadi, Connie W. Wang, Jennifer C. Lai, Srinivasan Dasarathy, Matthew R. Kappus, Michael A. Dunn, Elizabeth J. Carey, Aldo J. Montano‐Loza, From the Fitness, Life Enhancement, and Exercise in Liver Transplantation (FLEXIT) Consortium
Poor performance of psoas muscle index for identification of patients with higher waitlist mortality risk in cirrhosis
Sarcopenia, characterized by low muscle mass, associates with mortality in patients with cirrhosis. Skeletal muscle area in a single computed tomography image at the level of the third lumbar vertebrate (L3) is a valid representative of whole body muscle mass. Controversy remains regarding applicability of psoas muscle to identify patients at greater risk of mortality. We aimed to determine psoas muscle index (PMI) association with skeletal muscle index (SMI) and to evaluate the capacity of PMI to predict liver transplant waitlist mortality.
We evaluated listed adult patients with cirrhosis from 2012 to 2013 at four North American liver transplant centres. From L3 computed tomography images within 3 months of listing, we determined SMI and PMI expressed by cm2/m2. Low SMI was defined as SMI <39 cm2/m2 in women and <50 cm2/m2 in men as published by us earlier. Cut‐offs for PMI to predict mortality were established using a receiver‐operating characteristic analysis. Mortality predictors were determined using competing‐risk analysis with reported results as subdistribution hazard ratios (sHRs).
Of 353 waitlist candidates, 68% were men, mean age 56 ± 9 years, and Model for End‐stage Liver Disease of 16 ± 8 points. Low SMI was present more frequently in men than women (51 vs. 36%, P = 0.02). Moderately strong correlation between SMI and PMI was observed (r > 0.7, P < 0.001). Low PMI (males < 5.1 cm2/m2; females < 4.3 cm2/m2) yielded poor and moderate concordance with low SMI in men and women, respectively (Kappa coefficient 0.31 and 0.63). SMI (39 ± 9 vs. 43 ± 7 cm2/m2; P = 0.009) and PMI (4.4 ± 1.3 vs. 5.2 ± 1.1 cm2/m2; P = 0.001) were lower in women who died and/or were delisted (compared with non‐deceased patients) whereas men who died and/or were delisted had only lower SMI (47 ± 7 vs. 51 ± 9 cm2/m2; P = 0.003), but not PMI compared with non‐deceased patients. In women, both SMI (sHR 0.94, P = 0.048) and PMI (sHR 0.58, P = 0.002) were predictors of mortality, while in men, SMI was significant (sHR 0.95, P = 0.001) and PMI showed a trend to be (sHR 0.85, P = 0.09) associated with mortality. Overall, 104 patients (29%) were misclassified between SMI and PMI categories. Using PMI cut‐offs, 66% and 28% of low SMI men and women, who have a higher risk of mortality, were incorrectly classified as low risk.
Skeletal muscle index is a more complete and robust measurement than PMI, especially in men with cirrhosis. Low PMI identifies an incomplete subset of patients at increased risk of mortality indicated by low SMI. Given the poor performance of PMI, SMI should not be substituted by PMI.
Ebadi, M., Wang, C. W., Lai, J. C., Dasarathy, S., Kappus, M. R., Dunn, M. A., Carey, E. J., Montano-Loza, A. J., and From the Fitness, Life Enhancement, and Exercise in Liver Transplantation (FLEXIT) Consortium (2018) Poor performance of psoas muscle index for identification of patients with higher waitlist mortality risk in cirrhosis. Journal of Cachexia, Sarcopenia and Muscle, 9: 1053–1062. https://doi.org/10.1002/jcsm.12349.
Article first published online: 14 September 2018
Jessica González-Sánchez Agustín Sánchez-Temprano Tania Cid-Díaz Regina Pabst-Fernández Carlos S. Mosteiro Rosalía Gallego Ruben Nogueiras Xesús Casabiell Gillian S. Butler-Browne Vincent Mouly José Luis Relova Yolanda Pazos Jesús P. Camiña
Improvement of Duchenne muscular dystrophy phenotype following obestatin treatment
This study was performed to test the therapeutic potential of obestatin, an autocrine anabolic factor regulating skeletal muscle repair, to ameliorate the Duchenne muscular dystrophy (DMD) phenotype.
Methods and results
Using a multidisciplinary approach, we characterized the ageing-related preproghrelin/GPR39 expression patterns in tibialis anterior (TA) muscles of 4-, 8-, and 18-week-old mdx mice (n = 3/group) and established the effects of obestatin administration at this level in 8-week-old mdx mice (n = 5/group). The findings were extended to in vitro effects on human immortalized DMD myotubes. An analysis of TAs revealed an age-related loss of preproghrelin expression, as precursor of obestatin, in mdx mice. Administration of obestatin resulted in a significant increase in tetanic specific force (33.0% ± 1.5%, P < 0.05), compared with control mdx mice. Obestatin-treated TAs were characterized by reduction of fibres with centrally located nuclei (10.0% ± 1.2%, P < 0.05) together with an increase in the number of type I fibres (25.2% ± 1.7%, P < 0.05) associated to histone deacetylases/myocyte enhancer factor-2 and peroxisome proliferator-activated receptor-gamma coactivator 1a axis, and down-regulation of ubiquitin E3-ligases by inactivation of FoxO1/4, indexes of muscle atrophy. Obestatin reduced the level of contractile damage and tissue fibrosis. These observations correlated with decline in serum creatine kinase (58.8 ± 15.2, P < 0.05). Obestatin led to stabilization of the sarcolemma by up-regulation of utrophin, a-syntrophin, ß-dystroglycan, and a7ß1-integrin proteins. These pathways were also operative in human DMD myotubes.
These results highlight the potential of obestatin as a peptide therapeutic for preserving muscle integrity in DMD, thus allowing a better efficiency of gene or cell therapy in a combined therapeutic approach.
González‐Sánchez, J., Sánchez‐Temprano, A., Cid‐Díaz, T., Pabst‐Fernández, R., Mosteiro, C. S., Gallego, R., Nogueiras, R., Casabiell, X., Butler‐Browne, G. S., Mouly, V., Relova, J. L., Pazos, Y., and Camiña, J. P. (2018) Improvement of Duchenne muscular dystrophy phenotype following obestatin treatment. Journal of Cachexia, Sarcopenia and Muscle, 9: 1063–1078. https://doi.org/10.1002/jcsm.12338.
Article first published online: 18 October 2018
Lena Pinzur, Levent Akyuez, Lilia Levdansky, Michal Blumenfeld, Evgenia Volinsky, Zami Aberman, Petra Reinke, Racheli Ofir, Hans‐Dieter Volk, Raphael Gorodetsky
Rescue from lethal acute radiation syndrome (ARS) with severe weight loss by secretome of intramuscularly injected human placental stromal cells
Most current cell‐based regenerative therapies are based on the indirect induction of the affected tissues repair. Xenogeneic cell‐based treatment with expanded human placenta stromal cells, predominantly from fetal origin (PLX‐RAD cells), were shown to mitigate significantly acute radiation syndrome (ARS) following high dose irradiation in mice, with expedited regain of weight loss and haematopoietic function. The current mechanistic study explores the indirect effect of the secretome of PLX‐RAD cells in the rescue of the irradiated mice.
The mitigation of the ARS was investigated following two intramuscularly (IM) injected 2 × 106 PLX‐RAD cells, 1 and 5 days following 7.7 Gy irradiation. The mice survival rate and their blood or bone marrow (BM) cell counts were followed up and correlated with multiplex immunoassay of a panel of related human proteins of PLX‐RAD derived secretome, as well as endogenous secretion of related mouse proteins. PLX‐RAD secretome was also tested in vitro for its effect on the induction of the migration of BM progenitors.
A 7.7 Gy whole body mice irradiation resulted in ~25% survival by 21 days. Treatment with two IM injections of 2 × 106 PLX‐RAD cells on days 1 and 5 after irradiation mitigated highly significantly the subsequent lethal ARS, with survival rate increase to nearly 100% and fast regain of the initial weight loss (P < 0,0001). This was associated with a significant faster haematopoiesis recovery from day 9 onwards (P < 0.01). Nine out of the 65 human proteins tested were highly significantly elevated in the mouse circulation, peaking on days 6–9 after irradiation, relative to negligible levels in non‐irradiated PLX‐RAD injected mice (P < 0.01). The highly elevated proteins included human G‐CSF, GRO, MCP‐1, IL‐6 and lL‐8, reaching >500 pg/mL, while MCP‐3, ENA, Eotaxin and fractalkine levels ranged between ~60–160pg/mL. The detected radiation‐induced PLX‐RAD secretome correlated well with the timing of the fast haematopoiesis regeneration. The radiation‐induced PLX‐RAD secretome seemed to reinforce the delayed high levels secretion of related mouse endogenous cytokines, including GCSF, KC, MCP‐1 and IL‐6. Additional supportive in vitro studies also confirmed the ability of cultured PLX‐RAD secretome to induce accelerated migration of BM progenitors.
A well‐regulated and orchestrated secretion of major pro‐regenerative BM supporting secretome in high dose irradiated mice, treated with xenogeneic IM injected PLX‐RAD cells, can explain the observed mitigation of ARS. This seemed to coincide with faster haematopoiesis regeneration, regain of severe weight loss and the increased survival rate. The ARS‐related stress signals activating the IM injected PLX‐RAD cells for the remote secretion of the relevant human proteins deserve further investigation.
Pinzur, L., Akyuez, L., Levdansky, L., Blumenfeld, M., Volinsky, E., Aberman, Z., Reinke, P., Ofir, R., Volk, H.‐D., and Gorodetsky, R. (2018) Rescue from lethal acute radiation syndrome (ARS) with severe weight loss by secretome of intramuscularly injected human placental stromal cells. Journal of Cachexia, Sarcopenia and Muscle, 9: 1079–1092. https://doi.org/10.1002/jcsm.12342.
Article first published online: 16 September 2018
Alexandra Grimm, Heiko Meyer, Marcel D. Nickel, Mathias Nittka, Esther Raithel, Oliver Chaudry, Andreas Friedberger, Michael Uder, Wolfgang Kemmler, Klaus Engelke, Harald H. Quick
Repeatability of Dixon magnetic resonance imaging and magnetic resonance spectroscopy for quantitative muscle fat assessments in the thigh
Changes in muscle fat composition as for example observed in sarcopenia or muscular dystrophy affect physical performance and muscular function, like strength and power. The purpose of the present study is to measure the repeatability of Dixon magnetic resonance imaging (MRI) for assessing muscle volume and fat in the thigh. Furthermore, repeatability of magnetic resonance spectroscopy (MRS) for assessing muscle fat is determined.
A prototype 6-point Dixon MRI method was used to measure muscle volume and muscle proton density fat fraction (PDFF) in the left thigh. PDFF was measured in musculus semitendinosus of the left thigh with a T2-corrected multi-echo MRS method. For the determination of short-term repeatability (consecutive examinations), the root mean square coefficients of variation of Dixon MRI and MRS data of 23 young and healthy (29 ± 5 years) and 24 elderly men with sarcopenia (78 ± 5 years) were calculated. For the estimation of the long-term repeatability (13 weeks between examinations), the root mean square coefficients of variation of MRI data of seven young and healthy (31 ± 7 years) and 23 elderly sarcopenic men (76 ± 5 years) were calculated. Long-term repeatability of MRS was not determined.
Short-term errors of Dixon MRI volume measurement were between 1.2% and 1.5%, between 2.1% and 1.6% for Dixon MRI PDFF measurement, and between 9.0% and 15.3% for MRS. Because of the high short-term repeatability errors of MRS, long-term errors were not determined. Long-term errors of MRI volume measurement were between 1.9% and 4.0% and of Dixon MRI PDFF measurement between 2.1% and 4.2%.
The high degree of repeatability of volume and PDFF Dixon MRI supports its use to predict future mobility impairment and measures the success of therapeutic interventions, for example, in sarcopenia in aging populations and muscular dystrophy. Because of possible inhomogeneity of fat infiltration in muscle tissue, the application of MRS for PDFF measurements in muscle is more problematic because this may result in high repeatability errors. In addition, the tissue composition within the MRS voxel may not be representative for the whole muscle.
Grimm, A., Meyer, H., Nickel, M. D., Nittka, M., Raithel, E., Chaudry, O., Friedberger, A., Uder, M., Kemmler, W., Engelke, K., and Quick, H. H. (2018) Repeatability of Dixon magnetic resonance imaging and magnetic resonance spectroscopy for quantitative muscle fat assessments in the thigh. Journal of Cachexia, Sarcopenia and Muscle, 9: 1093–1100. https://doi.org/10.1002/jcsm.12343.
Article first published online: 3 October 2018
Nelson Inácio Pinto Neto, Ariene Soares de Pinho Murari, Lila Missae Oyama, José Pinhata Otoch, Paulo Sérgio Martins Alcântara, Flavio Tokeshi, Raquel Galvão Figuerêdo, Michele Joana Alves, Joanna Darck Carola Correia Lima, Emídio Marques de Matos‐Neto, Marilia Seelaender, Claudia Maria Oller do Nascimento
Peritumoural adipose tissue pro‐inflammatory cytokines are associated with tumoural growth factors in cancer cachexia patients
Cancer cachexia (CC) is a multifactorial syndrome, often irreversible, that affects patients with cancer influenced, in part, by the inflammatory condition. Peritumoural adipose tissue produces adipokines and angiogenic, apoptotic, and growth factors; given the possible crosstalk between the peritumoural adipose tissue and tumour, these may play an important role in cancer biology and carcinogenesis.
The aim of this study was to evaluate the factors produced by peritumoural adipose tissue in a cohort of 16 colorectal cancer patients with either weight‐stable cancer (WSC; n = 7) or CC (n = 9). The study was approved by the Ethics Research Committee (972.914). Samples of peritumoural adipose tissue were analysed for concentrations of TNF‐α, IL‐1β, STAT‐1, STAT‐3, RANTES, IL‐1Ra, IP‐10, IL‐15, MCP‐1, IFN‐α, GCSF, FADD, and TGF‐β. The cytokines and proteins were measured using Multiplex. Correlations between the proteins and cytokines were evaluated.
TNF‐α, STAT‐1, and FADD, a factor involved in apoptosis, were significantly higher in CC group than in the WSC group. In the peritumoural adipose tissue of the CC group, RANTES showed a significant positive correlation with IL‐1Ra and IP‐10 and a negative correlation with IFN‐α; and GCSF showed significant negative correlations with IL‐1Ra, IP‐10, IL‐15, and MCP‐1 and a positive correlation with IFN‐α. In the peritumoural adipose tissue of the WSC group, no significant correlations were detected between RANTES, GCSF, IL‐3, FADD, and STAT‐1 and the cytokines/chemokines analysed.
These results indicated that inflammatory and tumorigenic pathways were altered in peritumoural adipose tissue in CC. Furthermore, inflammatory cytokines were correlated with growth factors in the peritumoural adipose tissue of cachectic patients, suggesting that inflammatory cytokines modulated the proliferative environment closely linked to the tumour.
Neto, N. I. P., Murari, A. S. P., Oyama, L. M., Otoch, J. P., Alcântara, P. S. M., Tokeshi, F., Figuerêdo, R. G., Alves, M. J., Lima, J. D. C. C., Matos‐Neto, E. M., Seelaender, M., and Oller do Nascimento, C. M. (2018) Peritumoural adipose tissue pro‐inflammatory cytokines are associated with tumoural growth factors in cancer cachexia patients. Journal of Cachexia, Sarcopenia and Muscle, 9: 1101–1108. https://doi.org/10.1002/jcsm.12345.
Article first published online: 30 September 2018
Susan C. Kandarian, Rachel L. Nosacka, Andrea E. Delitto, Andrew R. Judge, Sarah M. Judge, John D. Ganey, Jesse D. Moreira, Robert W. Jackman
Tumour‐derived leukaemia inhibitory factor is a major driver of cancer cachexia and morbidity in C26 tumour‐bearing miceBackground
Cancer cachexia is a metabolic wasting syndrome that is strongly associated with a poor prognosis. The initiating factors causing fat and muscle loss are largely unknown. Previously, we found that leukaemia inhibitory factor (LIF) secreted by C26 colon carcinoma cells was responsible for atrophy in treated myotubes. In the present study, we tested whether C26 tumour‐derived LIF is required for cancer cachexia in mice by knockout of Lif in C26 cells.
A C26 Lif null tumour cell line was made using CRISPR‐Cas9. Measurements of cachexia were compared in mice inoculated with C26 vs. C26Lif−/− tumour cells, and atrophy was compared in myotubes treated with medium from C26 vs. C26Lif−/− tumour cells. Levels of 25 cytokines/chemokines were compared in serum of mice bearing C26 vs. C26Lif−/− tumours and in the medium from these tumour cell lines.
At study endpoint, C26 mice showed outward signs of sickness while mice with C26Lif−/− tumours appeared healthy. Mice with C26Lif−/− tumours showed a 55–75% amelioration of body weight loss, muscle loss, fat loss, and splenomegaly compared with mice with C26 tumours (P < 0.05). The heart was not affected by LIF levels because the loss of cardiac mass was the same in C26 and C26Lif−/− tumour‐bearing mice. LIF levels in mouse serum was entirely dependent on secretion from the tumour cells. Serum levels of interleukin‐6 and G‐CSF were increased by 79‐fold and 68‐fold, respectively, in C26 mice but only by five‐fold and two‐fold, respectively, in C26Lif−/− mice, suggesting that interleukin‐6 and G‐CSF increases are dependent on tumour‐derived LIF.
This study shows the first use of CRISPR‐Cas9 knockout of a candidate cachexia factor in tumour cells. The results provide direct evidence for LIF as a major cachexia initiating factor for the C26 tumour in vivo. Tumour‐derived LIF was also a regulator of multiple cytokines in C26 tumour cells and in C26 tumour‐bearing mice. The identification of tumour‐derived factors such as LIF that initiate the cachectic process is immediately applicable to the development of therapeutics to treat cachexia. This is a proof of principle for studies that when carried out in human cells, will make possible an understanding of the factors causing cachexia in a patient‐specific manner.
Kandarian, S. C., Nosacka, R. L., Delitto, A. E., Judge, A. R., Judge, S. M., Ganey, J. D., Moreira, J. D., and Jackman, R. W. (2018) Tumour‐derived leukaemia inhibitory factor is a major driver of cancer cachexia and morbidity in C26 tumour‐bearing mice. Journal of Cachexia, Sarcopenia and Muscle, 9: 1109–1120. https://doi.org/10.1002/jcsm.12346.
Article first published online: 18 November 2018
Susan C. Kandarian, Rachel L. Nosacka, Andrea E. Delitto, Andrew R. Judge, Sarah M. Judge, John D. Ganey, Jesse D. Moreira, Robert W. Jackman
(2018), Abstracts of the 11th International Conference on Cachexia, Sarcopenia and Muscle Wasting, Maastricht, The Netherlands, 7–9 December 2018. Journal of Cachexia, Sarcopenia and Muscle, 9: 1121-1184. doi:10.1002/jcsm.12365
Thank You to Reviewers
(2018), With Appreciation. Journal of Cachexia, Sarcopenia and Muscle, 9: 1185-1186. doi:10.1002/jcsm.12367