Cancer cachexia is a complex syndrome that can affect up to 80% of cancer patients. Among the symptoms involved in cancer cachexia progression, the establishment of a systemic inflammation and the imbalance in glucose metabolism homeostasis take an important part in this profile. The aim of the present study was to further evaluate the role of cancer-induced inflammation in the impairment of pancreatic beta cell function in solid Ehrlich carcinoma-bearing mice. For that, we have focused the study in the pro-inflammatory mechanisms involved on β-cell death. We have observed that tumor-bearing animals developed an aggressive pancreatic inflammatory status 14 days after tumor cells inoculation. The increase of pro-inflammatory cytokines followed by an up-regulation of important transcription factors such as NF-κB and STAT-1 and its related genes, reveled a similar outline for β-cell death found in type 1 diabetes. Furthermore, expression of pro-apoptotic Bcl-2 family members followed by caspases activation was increased in pancreatic islets of tumor-bearing animals and the expression of anti-apoptotic members was decreased. We have also observed an increase in β-cell death and ER stress components, as well as a decrease in insulin content cells together with an increase in alpha cells content. Overall, our results provide strong evidences that pancreatic β-cells in tumor-bearing animals are widely affected by tumor presence and systemic inflammation establishment. Interestingly, it was shown a similarity with mechanisms of β-cell death found in type 1 diabetes. Although the exactly mechanisms behind the changes found in carbohydrate metabolism in cancer cachexia is still unclear, our data can help to clarify, at least in part, this profile and would serve as a basis for development of new strategies to prevent cachexia progression and to improve the quality of life of cancer patients. / Doctorat en Sciences biomédicales et pharmaceutiques (Médecine) / info:eu-repo/semantics/nonPublished

Indianapolis / By the traditional definition of unintended weight loss, cachexia develops in ~80% of patients with pancreatic ductal adenocarcinoma (PDAC). Here we measure the longitudinal body composition changes in patients with advanced PDAC undergoing FOLFIRINOX therapy. We performed a retrospective review of 53 patients with advanced PDAC on FOLFIRINOX as first line therapy at Indiana University Hospital from July 2010 to August 2015. Demographic, clinical, and survival data were collected. Body composition measurement, trend, univariate and multivariate analysis were performed. Three cachexia phenotypes were identified. The majority of patients, 64%, had Muscle-and-Fat Wasting (MFW), while 17% had Fat-Only Wasting (FW) and 19% had No Wasting (NW). NW had significantly improved overall median survival (OMS) of 22.6 months vs. 13.0 months for FW and 12.2 months for MFW (p=0.02). FW (HR=5.2; 95%CI=1.5-17.3) and MFW (HR=1.8; 95%CI=1.1-2.9) were associated with an increased risk of mortality compared to NW. OMS and risk of mortality did not differ between FW and MFW. Progression of disease, sarcopenic obesity at diagnosis, and primary tail tumors were also associated with decreased OMS. On multivariate analysis cachexia phenotype and chemotherapy response were independently associated with survival. Three phenotypes of cachexia were observed. Moreover, three phenotypes suggests molecular or genetic heterogeneity of host or tumor. Identifying these differences will be vital to defining optimal treatment for cachexia. Survival among FW was as poor as MFW suggesting adipose tissue plays a crucial role in cachexia. Blunting or possibly preventing cachexia may confer a significant survival advantage in patients with advanced PDAC.

Indiana University-Purdue University Indianapolis (IUPUI) / The ability to preserve, protect, or grow skeletal muscle would greatly benefit patients in health and disease. Understanding the molecular pathways that regulate muscle size is necessary to develop interventions. The extracellular signal-related kinase (ERK) and Hedgehog signaling pathways each play necessary roles in skeletal muscle development. The ERK pathway has been shown to both stimulate and inhibit muscle development at different stages, while Hedgehog signaling is vital for embryonic muscle development. Thus, these pathways represent prime targets for manipulation in diseases associated with muscle loss. In prior studies, cancer patients treated with the ERK inhibitor, Selumetinib, experienced significant gains in lean body mass. To study the mechanisms responsible, we tested the potential of Selumetinib to protect against muscle wasting in muscle cell cultures and in mice with experimental lung cancer. Selumetinib was able to induce hypertrophy of cultured muscle cells. In mice, we observed a reduction in tumor mass and in circulating mediators of muscle wasting including inflammatory cytokines. However, Selumetinib treatment did not prevent cancer-induced muscle loss. Together, these data suggest a diversity in the underlying molecular mechanisms and the need for careful consideration when extrapolating results across different disease states, clinical trials, and model systems. In separate studies, we found that the Hedgehog pathway was increased in mice and patients with cancer-associated muscle wasting and inflammation. In a series of studies in muscle cell cultures, in genetically modified mice, and in mice bearing tumors, we found that inflammatory cytokines activated Hedgehog expression in muscle. Hedgehog signaling promoted the replication of muscle stem cells but reduced the expression of genes that specify mature muscle. Inhibiting Hedgehog signaling promoted muscle growth, while activating it caused muscle wasting. Furthermore, we identified unique properties of two proteins activated by Hedgehog, Gli1 and Gli2, where Gli1 appears to promote muscle stem cell proliferation and Gli2 mature muscle gene expression. These data implicate the Hedgehog pathway, GLI1 and GLI2 as targets for treatment of muscle wasting diseases. / 2 years

Indiana University-Purdue University Indianapolis (IUPUI) / Cachexia, the involuntary loss of fat and muscle is associated with pancreatic ductal adenocarcinoma (PDAC), contributing to its 90% 5-year mortality rate. Elevated Interleukin-6 (IL-6) expression is associated with cachexia severity and reduced survival in patients. IL-6 in cancer is well documented, but IL-6 signaling crosstalk among tissues is not. IL-6 signals by binding membrane-bound IL-6 receptor (IL-6R) (classical signaling) or soluble IL- 6R (sIL6R; trans-signaling) produced by shedding of the membrane receptor primarily from muscle, liver and leukocytes. Herein I investigate the role of tumorderived IL-6 on muscle and fat crosstalk in PDAC. Loss of IL-6 expression in murine KPC PDAC cells was accomplished by CRISPR/Cas9 mutagenesis of the Il6 gene. Orthotopic KPC IL-6 knockout (KPC-IL-6KO) tumor-bearing mice had reduced cachexia, with attenuated fat loss and no significant muscle loss, and longer survival versus KPC controls. Only KPC tumor-bearing mice had significant myosteatosis, aberrant branched chain amino acid and fatty acid metabolism, and reduced pyruvate entry into the TCA-cycle, determined by increased pyruvate dehydrogenase kinase 4 (PDK4) expression in muscle. Muscle was a main source of sIL6R, and fat a primary contributor of IL-6 in KPC tumor-bearing mice. Myosteatosis leads to activation of lipid-sensitive kinases like protein kinase C theta (PKCθ, gene name Prkcq) in muscle. KPC tumorbearing mice had increased muscle PKCθ activation, and PKCθ is known to regulate metabolism and inflammation. Prkcq-/- KPC tumor-bearing mice had reduced cachexia and maintained muscle mass and force production versus wild type tumor-bearing mice. Together these data implicate progressive signaling mechanisms whereby tumor-derived IL-6 is associated with increased muscle IL6R expression and fat lipolysis, promoting myosteatosis and muscle PKCθ activation, ultimately increasing cachexia severity in PDAC. / 2021-11-03

Cancer cachexia is a wasting syndrome causing involuntary weight loss and muscle atrophy. PARP1 is a nicotinamide dinucleotide-dependent enzyme that modifies target proteins by PARylation. The reversal process, dePARylation, is mediated by the PARG enzyme. PARP1 inhibitors are potent cancer agents, while PARG inhibitors are in clinical trials for similar cancers. Here we examine the role of PARylation on muscle homeostasis in cancer cachexia. We employed mouse models with inducible muscle specific knockouts of Parp1 (Parp1-IMKO) or Parg (Parg-IMKO) to investigate their implications on skeletal muscle in a cancer cachexia model. We assessed muscle loss, grip strength, and gene expression. Results show that Parp1- IMKO mice had increased muscle wasting, while Parg-IMKO had degradation rates similar to wild-type mice during cancer cachexia. This suggests reduced PARylation might worsen cancer cachexia, while an increase does not. This supports PARG inhibitor development as anticancer alternatives. Our study highlights challenges with PARP1 inhibitors and the need to study PARylation and dePARylation in muscle health during cancer cachexia, impacting clinical strategies using PARP1 or PARG inhibitors.

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Muscle wasting and increased proteolysis is a major problem in chronic kidney disease (CKD). Exercise is potentially beneficial, but has been under-investigated in pre-dialysis CKD and could theoretically worsen acidosis through exercise-induced lactic acid generation. We therefore investigated effects of 6 months walking exercise with and without additional alkali therapy. 40 patients were recruited (23 male and 17 female, median age 58, range 20-83, mean eGFR±SEM 25.7±1.2ml/min/1.73m2). 20 undertook walking exercise at a Borg Rating of Perceived Exertion Rate (RPE) of 12-14 for at least 30 minutes, 5 times a week. The other 20 continued with normal physical activity (non-exercising controls). In addition to standard oral bicarbonate therapy (STD), 10 patients in each group were randomised to receive additional bicarbonate (XS). Blood and vastus lateralis muscle biopsies were drawn at baseline, one and six months. 18 exercisers (including 8 in XS group) and 14 controls (6 in XS group) completed the 6 month study. Exercise tolerance increased after 1 and 6 months in the exercisers, but not the controls, accompanied by a reduced acute lactate response in the XS, but not the STD exercising group. After 6 months of exercise, 9 intramuscular free amino acids showed striking depletion in the STD, but not XS bicarbonate group. This suggests an inhibition of active amino acid transporters, possibly the SNAT2 transporters that are inhibited by acidosis. Studies with cultured myotubes identified glucocorticoid as a possible mediator of acid s inhibitory effect on SNAT2. The preservation of amino acid concentrations in the XS exercising group was accompanied by strong suppression of ubiquitin E3-ligases MuRF-1 and MAFbx which activate proteolysis through the ubiquitin-proteasome pathway. However, other anabolic indicators (Protein Kinase B activation and suppression of the 14kDa actin fragment) were unaffected in the exercising XS group. Possibly because of this, overall suppression of myofibrillar proteolysis (3-methyl histidine excretion) and increased lean body mass (DEXA) were not observed in the exercising patients. As XS alkali had no effect in non-exercisers, it is concluded that alkali effects in the exercisers arose by countering exercise-induced acidosis. Sulphuric acid produced from the catabolism of sulphur-containing amino acids ingested in the diet is the main contributor to the daily titratable acid load and hence acidosis in CKD. In these patients the amount of sulphate excreted in urine over 24h varied widely between individuals. This directly correlated with 3-methyl histidine excretion suggesting that sulphate excretion may be a better clinical indicator of acidotic patients at long-term risk of cachexia than conventional measures such as venous bicarbonate. Studies with cultured myotubes confirmed that skeletal muscle is a source of sulphuric acid and showed that production of this acid is partly suppressed by L-Glutamine a potential novel way to control acidosis in CKD.

A redução do consumo de alimentos é freqüente durante a descompensação da insuficiência cardíaca, quando há um aumento do gasto energético basal. Os triglicérides de cadeia média, utilizados como suplementação energética, aumentam a densidade calórica dos alimentos, contribuindo para o metabolismo energético dos pacientes com insuficiência cardíaca. O objetivo foi avaliar o efeito da suplementação de triglicérides de cadeia média sobre o quoeficiente respiratório, na insuficiência cardíaca congestiva e na baixa ingestão alimentar. Foi realizado um estudo randomizado aberto com 45 pacientes de 18 a 70 anos com insuficiência cardíaca congestiva descompensada, fração de ejeção < 0,45, sem drogas vasoativas, dieta oral, IMC < 25kg/m2 para adultos e < 27 kg/m2 para idosos. Foram alocados aleatoriamente para grupo com suplementação de TCM e grupo controle. Os grupos realizaram duas medidas de VCO2 e VO2, por calorimetria indireta. O QR foi avaliado pela análise de variância com medidas repetidas. Foi considerado significante P < 0,05. 75% dos pacientes foram identificados em eutrofia pelo IMC, porém destes, 67% foram diagnosticados com desnutrição calórica e 65% com desnutrição protéico calórica quando analisados e classificados os indicadores de dobras cutâneas. A proporção de lipídeos aumentou de 9,5% para 57% das recomendações com 236,7 ± 95,0 kcal/d do triglicérides de cadeia média (P <0,001). A ingestão de calorias aumentou de 1966,3 ± 643,3 kcal /d para 2202,7 ± 708,4 kcal /d no grupo intervenção e manteve 1960,7 ± 702,6 kcal /d no grupo controle. Não houve variação significativa quoeficiente respiratório (grupo triglicérides de cadeia média +0,4%; grupo controle: +2,5%, P = 0,458). Quatro pacientes apresentaram efeitos adversos ao suplemento, no entanto, sem necessidade de suspensão. O triglicéride de cadeia média não reduziu o quoeficiente respiratório, no entanto melhorou a proporção de carboidratos e lipídios, contribuindo para a melhora do aproveitamento energético. / Food intake reduction is frequent during decompensation of heart failure, when basal energy expenditure increases. In addition, medium chain triglycerides are used as energy supplementation increases caloric density of food, contributing to energy metabolism of patients with heart failure. The objective was to evaluate the effect of supplementation of medium chain triglycerides on the respiratory coefficient in congestive heart failure and low food intake. We conducted a randomized open label study with 45 patients from 18 to 70 years old with decompensated congestive heart failure, ejection fraction < 0,45, without intravenous inotropic drugs, oral diet and body mass index < 25 kg/m2 for adults and <27 kg/m2 for the elderly Patients were randomly allocated to supplementation with medium chain triglycerides or control group. They were submitted to two measurements of VCO2 and VO2 by indirect calorimetry. Analysis of variance with repeated measures analyzes respiratory coefficient change and two-sided. P< 0,05 was significant. 75% of patients were identified in eutrophic by body mass index, but these, 67% were diagnosed with calorie malnutrition and 65% with protein calorie malnutrition when analyzed and classified by skinfolds measures. Adequate proportion of carbohydrates and lipids increased from 9,5% to 57% of patients with 236,7 ± 95,0 kcal/d of medium chain triglycerides (P<0,001). Caloric intake increased from 1966,3 ± 643,3 kcal/d to 2202,7 ± 708,4 kcal/d in the medium chain triglycerides group and remained 1960,7 ± 702,6 kcal/d in control group. There was not a significant respiratory coefficient variation (medium chain triglycerides group +0,4%; control group: +2,5%; P=0,458). Four patients presented adverse effects with medium chain triglycerides; however, without requirement of withdrawal. Medium chain triglycerides did not reduce respiratory coefficient, however they improved carbohydrates and lipids proportion, contributing to improvement of energy utilization.

This thesis presents Pathway Informed Analysis (PIA), a classification method for predicting disease states (diagnosis) from metabolic profile measurements that incorporates biological knowledge in the form of metabolic pathways. A metabolic pathway describes a set of chemical reactions that perform a specific biological function. A significant amount of biological knowledge produced by efforts to identify and understand these pathways is formalized in readily accessible databases such as the Kyoto Encyclopedia of Genes and Genomes. PIA uses metabolic pathways to identify relationships among the metabolite concentrations that are measured by a metabolic profile. Specifically, PIA assumes that the class-conditional metabolite concentrations (diseased vs. healthy, respectively) follow multivariate normal distributions. It further assumes that conditional independence statements about these distributions derived from the pathways relate the concentrations of the metabolites to each other. The two assumptions allow for a natural representation of the class-conditional distributions using a type of probabilistic graphical model called a Gaussian Markov Random Field. PIA efficiently estimates the parameters defining these distributions from example patients to produce a classifier. It classifies an undiagnosed patient by evaluating both models to determine the most probable class given their metabolic profile. We apply PIA to a data set of cancer patients to diagnose those with a muscle wasting disease called cachexia. Standard machine learning algorithms such as Naive Bayes, Tree-augmented Naive Bayes, Support Vector Machines and C4.5 are used to evaluate the performance of PIA. The overall classification accuracy of PIA is better than these algorithms on this data set but the difference is not statistically significant. We also apply PIA to several other classification tasks. Some involve predicting various manipulations of the metabolic processes performed in experiments with worms. Other tasks are to classify pigs according to properties of their dietary intake. The accuracy of PIA at these tasks is not significantly better than the standard algorithms.