Cachexia Syndrome Research Articles

A Pound of Flesh: What Cachexia Is and What It Is Not.

Body weight loss, mostly due to the wasting of skeletal muscle and adipose tissue, is the hallmark of the so-called cachexia syndrome. Cachexia is associated with several acute and chronic disease states such as cancer, chronic obstructive pulmonary disease (COPD), heart and kidney failure, and acquired and autoimmune diseases and also pharmacological treatments such as chemotherapy. The clinical relevance of cachexia and its impact on patients’ quality of life has been neglected for decades. Only recently did the international community agree upon a definition of the term cachexia, and we are still awaiting the standardization of markers and tests for the diagnosis and staging of cancer-related cachexia. In this review, we discuss cachexia, considering the evolving use of the term for diagnostic purposes and the implications it has for clinical biomarkers, to provide a comprehensive overview of its biology and clinical management. Advances and tools developed so far for the in vitro testing of cachexia and drug screening will be described. We will also evaluate the nomenclature of different forms of muscle wasting and degeneration and discuss features that distinguish cachexia from other forms of muscle wasting in the context of different conditions.

Vochysia tucanorum Mart. butanol fraction presents antitumoral activity in vivo and prevents the installation of cachexia in solid Ehrlich tumor model

BackgroundCancer is a multifactorial disease caused by uncontrolled proliferation of cells. About 50–80% of cancer patients develop cachexia, a complex metabolic syndrome associated with an increase of mortality and morbidity. However, there are no effective therapies in medical clinic for cancer cachexia. Vochysia tucanorum Mart. is a common three of the Brazilian “Cerrado”. The butanolic fraction of V. tucanorum (Fr-BuVt), very rich in triterpenes with various biological activities, might be interesting in being tested in cancer cachexia syndrome. Hence, the present study was undertaken to investigate the antitumoral activity of Fr-BuVt and its potential against cachexia development.MethodsEhrlich tumor was used as model of cancer cachexia. Ascitic Ehrlich tumor cells were collected, processed and inoculated subcutaneously in saline solution (1 × 107/100 μl; ≥95% viability) for the obtention of solid Ehrlich carcinoma. After inoculation, solid Ehrlich carcinoma-bearing mice were treated by 14 consecutive days by gavage with Fr-BuVt (200 mg/kg). Body weight and tumor volume were measure during the treatment period. Tumors were removed, weighed and properly processed to measure the content and phosphorylation levels of key-proteins involved to apoptotic and proliferation process by Western Blot. Muscles and adipose tissues were removed for weighed. Serum was collected to cytokines levels and energetic blood markers measurements.ResultsThe treatment with the Fr-BuVt (200 mg/kg, 14 days) decreased the solid Ehrlich tumor volume and weight besides increased the expression of the pro-apoptotic proteins caspase-3 and BAX, but also decreased the expression of the proteins involved in proliferation NFκB, mTOR and ERK. In addition, our data shows that the administration of Fr-BuVt was able to prevent the installation of cancer cachexia in Ehrlich carcinoma-bearing mice, since prevented the loss of body weight, as well as the loss of muscle and adipose tissue. Moreover, an improvement in some blood parameters such as decrease in cytokines TNF-α and IL-6 levels is observed.ConclusionsThe study revealed that Fr-BuVt has antitumoral activity and prevent installation of cancer cachexia in Ehrlich model. Therefore, Fr-BuVt may represent an alternative treatment for cancer cachexia.

Virtual Teaming: Leveraging Team Science Sense-Making During COVID-19.

Individuals with cancer anorexia cachexia syndrome (CACS) experience multifaceted distress. To address CACS patient concerns regarding their experience of care, our cancer center established a specialized CACS clinic in 2016. We applied the team science principle of the team mental model (TMM) to support development of an effective interprofessional collaborative CACS care team. In 2020, cessation of CACS clinic in-person visits during coronavirus disease 2019 (COVID-19) threatened the viability of the entrenched TMM and once again jeopardized the patient experience of care.We present a case-based vignette as a representative composite of patient experiences to illustrate the challenges. A 48-year-old female was referred to our CACS clinic for pancreatic cancer-associated appetite and weight loss during COVID-19. To reduce risk of infection, in-person clinic visits were curtailed. When informed about the resulting need to defer the CACS assessment, the patient and her spouse expressed concern that postponement would adversely affect her ability to undergo anticancer treatments or achieve beneficial outcomes.To minimize delays in CACS treatment and optimize the patient experience of care, we applied the team science principle of sense-making to help the team rapidly reformulate the TMM to provide interprofessional collaborative CACS care via telemedicine. The sense-making initiative highlights opportunities to examine sense-making within health care teams more broadly during and after the pandemic. The application of sense-making within interprofessional cancer care teams has not been described previously.

Nurses' Knowledge in Relation to the Anorexia-Cachexia Syndrome in Cancer Patients: A Cross-National Comparison in Two European Countries.

IntroductionThe Anorexia–Cachexia Syndrome (ACS) is a severe complication of cancer and is considered to be a significant cause of morbidity and mortality affecting up to two-thirds of cancer patients and one that needs specialized nursing care. Studies showed that the ACS has been relatively under-researched and under-resourced whist the nurses’ knowledge has not been systematically explored.ObjectiveΤo explores nurses’ knowledge, understanding, and management of ACS in clinical practice in two European countries.MethodsDescriptive-comparative study with 197 cancer nurses recruited during two National Conferences in Greece and Cyprus. Data were retrieved with the “Investigation of anorexia–cachexia syndrome in Practice” questionnaire.ResultsIn terms of nurses’ perceptions on ACS, the prevailing characteristic reported in both countries was anorexia (p = .65) followed by weight loss (p = .04). 189 nurses (95.9%, p = .176) do not currently use a tool to assess patients’ nutritional status as part of their standard clinical practice. Statistically significant differences were found in relation to the routine assessment of nutritional-related symptoms including early satiety (Cyprus 64% vs. Greece 37%, p = .001), hiccough (66% vs. 36%, p < .001), alteration of the taste/odor sensation (77% vs. 45%, p < .001), problems in the oral cavity (84% vs. 68%, p = .032) and daily activities (85% vs. 69%, p = .032). The priority level for the ACS management differed significantly in the two countries (p = .006), with higher priority being reported in Cyprus.ConclusionThe study showed that more education is needed for cancer nurses to better understand the ACS which can facilitate the better management of the syndrome in clinical practice.

Anorexia-cachexia syndrome in cancer patients: pathogenetic aspects and treatment options

Background. Modern standards for the treatment of both solid tumors and tumors of the blood system provide a mandatory assessment of the objective status of the patient. One of the important criteria of which is nutritional status. Underestimating the role of nutritional support in the treatment of cancer patients leads to a deterioration of treatment results due to the progressive deterioration of nutritional status and the development of cancer anorexia cachexia syndrome (CACS), which is an independent adverse factor leading to the death of the patient. The increase in the number of cancer patients with risk factors for CACS development requires not only close attention of clinicians to this problem, but also the development of clear recommendations for the diagnosis and management of such patients. This can contribute to solving several problems at once. First, it will allow optimizing monitoring of cancer patients predisposed to CACS development during anticancer treatment. Secondly, it will provide an opportunity to develop a diagnostic algorithm to prevent it. Third, the use of the identified criteria for predicting and outcome of complications both on an outpatient basis and in a hospital will be aimed at creating favorable conditions for anticancer therapy and thereby improving long-term treatment results and patients quality of life. Studying the mechanisms of development of CACS, the possibilities of correcting this condition, indicate the need for a multimodal concept and the rejection of the search for a “magic pill”. The results of a multicenter, prospective randomized study conducted in the oncology and hematology departments of healthcare institutions.Objective: to evaluate the effectiveness of FortiCare oral nutritional support in cancer patients under the real clinical practice.Materials and methods. The study included 96 patients with stage II–IV tumors. Radiation therapy was received by 28 patients, chemotherapy ‒ by 68 patients. Patient information was collected using an individual registration card. The patients were randomized according to nutritional support tactics (1:1). In the study group, with radiation (n = 14) and chemotherapy (n = 34), patients received enteral nutrition Forticare orally 125 ml 3 times a day in parallel with their usual diet. Patients in the control group during radiation therapy (n = 14) received the required amount of calories from their usual diet. During chemotherapy, patients in the control group (n = 34) with a lack of daily calorie intake received additional parenteral nutrition.Results and conclusion. While taking FortiCare, there was a smaller loss of body weight (p ≤0.05), a frequency of mucositis of the oral cavity, and esophagitis (p &gt;0.05). With chemotherapy, the incidence of diarrhea (p &lt;0.001) and constipation (p &lt;0.05) was detected less frequently than in the control group. A decrease in the frequency of hematological toxicity (leukopenia, thrombocytopenia) was noted (p &gt;0.05).

Botryosphaeran, a (1 → 3)(1 → 6)-β-D-glucan, reduces tumor development and cachexia syndrome in obese male rats by increasing insulin sensitivity and FOXO3a activity

Obesity is an important risk factor in tumor development. Botryosphaeran, a (1 → 3)(1 → 6)-β-D-glucan, produced by the fungus Botryosphaeria rhodina (MAMB-05), is a high molecular mass, water-soluble exopolysaccharide. It consists of a main chain of (1 → 3)-linked β-d-glucose units, with a degree of branching of ~22% at carbon-6 with glucose and gentiobiose residues linked through β-(1 → 6)-bonds, and presents a triple helix conformation. Botryosphaeran presents anticlastogenic, antiproliferative, pro-apoptotic and anti-obesogenic activities. This study evaluated the effects of botryosphaeran on tumor development in obesity and analyzed its mechanism of action. Obesity was induced in male Wistar rats by a high-fat/high-sugar diet. After 9 weeks, rats were divided into two groups: Obese Tumor (OT) and Obese Tumor Botryosphaeran (OTB), and inoculated with 1 × 107 Walker-256 tumor cells, and treatment with botryosphaeran (30 mg/kg b.w./day via gavage for 15 days) commenced. On the 11th week, biological parameters, tumor development, metabolic profile, erythrogram and protein expression were evaluated. Botryosphaeran significantly reduced tumor growth, body-weight loss and cachexia. Furthermore, botryosphaeran decreased mesenteric fat and insulin resistance, corrected macrocytic anemia, and increased Forkhead transcription factor-3a (FOXO3a) activity. Our study demonstrated the potential role of botryosphaeran in the management of cancer in tumor-bearing obese rats by increasing insulin sensitivity and FOXO3a activity.

Cannabis alleviates neuropathic pain and reverses weight loss in diabetic neuropathic cachexia in a previous heroin abuser.

SummaryTen years after the successful withdrawal from heroin abuse, a person with diabetes suffered intractable pain and severe muscular emaciation consistent with the syndrome of diabetic neuropathic cachexia. Anti-neuropathic medications failed neither to alleviate suffering and reverse weight loss, nor to stop muscular emaciation. Vigilant evaluation for weight loss aetiologies revealed no responsible aetiology. Prescribing medical cannabis became mandatory, with the intention to alleviate neuropathic pain, regain muscular mass and strengthen legs, enable standing upright and walking normally. Medical cannabis for pain-relief, and the orexigenic properties of tetrahydrocannabinol (THC) ingredient successfully achieved these goals.Learning points:Medical cannabis can serve to promptly alleviate severe diabetic neuropathic pain.Past history of heroin abuse was not an absolute contraindication to medical cannabis use.Medical cannabis increased appetite and reversed muscular emaciation.Medical cannabis decreased chronic pain and hence, its catabolic consequences.

Abstract PO-070: What kills patients with severe Covid-19 might also kill patients with terminal cancer

Abstract Introduction: As a prominent clinical feature of severe Covid-19, cytokine storm has attracted enormous attention recently. It is generally believed that cytokine storm might be the underlying force leading to health exacerbation and death from severe Covid-19. However, the role of cytokine storm in terminal cancer has not been reported. In this study, we investigated the role of cytokine storm in a murine tumor model that mimics the disease progression of terminal cancer. We found that cytokine storm develops in terminal cancer and leads to cachexia, which is a prevalent and lethal syndrome of terminal cancer. Methods: 7-week old BALB/c mice were inoculated with 1 x106 C26 tumor cells subcutaneously. Mice body weight and health condition were monitored starting 7 days after tumor inoculation. At various time points, serum cytokines were measured, immune cells were analyzed with flow cytometry, and multiple organs were collected and processed for histopathologic assessment. Results: Growth of subcutaneously inoculated tumors without metastasis progressively induces host body weight loss and overall health deterioration. Cytokine storm characterized by elevated expression of multiple proinflammatory cytokines such as IL-1, IL-6, and TNF-a in blood develops accompanying the health deterioration. In parallel with cytokine storm development, massive infiltration of Gr-1 positive cells occurs in vital organs (lung and liver) and brings severe tissue damage. Histopathologic check ruled out any tumor metastasis to these organs, which suggests that the inflammatory response is the cause of the multiple organ damage. Importantly, suppression of the inflammatory response with interventions can completely reverse the cachexia syndrome and increase survival. Conclusions and Implication: Cytokine storm develops and plays an important role in the health exacerbation of terminal cancer. Therefore, calming the cytokine storm with interventions that can suppress the inflammatory response might represent a new and promising approach to the treatment of terminal cancer. This approach may have the potential to save many patients from imminent deaths, which are often not directly caused by organ occupation. Citation Format: Lingbing Zhang. What kills patients with severe Covid-19 might also kill patients with terminal cancer [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr PO-070.

Asprosin is associated with anorexia and body fat mass in cancer patients.

Increasing evidence suggests that many adipokines are involved in cancer-related anorexia and cachexia syndrome (CACS), although the underlying mechanism remains to be clarify. Asprosin is a new peptide hormone mainly secreted by white adipose tissues that can increase appetite and body weight. In this cross-sectional study, we tested whether asprosin may intervene in the development of CACS. The fasting plasma asprosin levels were determined via enzyme-linked immune-sorbent assay. Anorexia was determined using the anorexia/cachexia subscale (A/CS) of the functional assessment of anorexia/cachexia therapy (FAACT) questionnaire. The body composition was assessed using bioelectrical impedance analysis. The association of plasma asprosin with anorexia, cachexia, and nutritional status was analyzed. One hundred twenty treatment-naïve patients with pathological confirmed gastrointestinal or lung cancer and 14 mild gastritis patients were recruited. We found no significant difference in asprosin levels between subgroups of patients by age, sex, cancer types or stage. Correlation analysis suggested that asprosin levels were positively associated with body fat mass (r = 0.248, p = 0.043). No correlations were found between asprosin levels and hemoglobin, white blood cell count, blood platelet count, albumin, C-reactive protein, glucose, cholesterol, triglyceride, high density lipoprotein, low density lipoprotein, body mass index, body fat percentage, protein, skeletal muscle, muscle mass, lean body mass, and basal metabolic rate. Furthermore, asprosin levels were not significantly different between patients with or without cachexia. However, patients with anorexia had significantly lower asprosin levels compared with patients without anorexia. No significant difference in asprosin levels between gastritis and gastric cancer patients. Similarly, no significant change of asprosin levels occurred postoperatively in 10 gastric cancer patients. Patients with anorexia had significantly lower asprosin levels compared with patients without anorexia. We therefore speculated that asprosin might intervene in the development of cancer anorexia and serve as a potential therapeutic target.

Botryosphaeran Attenuates Tumor Development and the Cancer Cachexia Syndrome in Walker-256 Tumor-Bearing Obese Rats and Improves the Metabolic and Hematological Profiles of These Rats

Studies demonstrate that obesity can increase tumor development. Botryosphaeran, a fungal (1→3)(1→6)-β-D-glucan, presents antimutagenic, antiproliferative and pro-apoptotic activities. This study evaluated the effects of botryosphaeran on tumor development and metabolic and hematological parameters in tumor-bearing obese and non-obese rats. Obesity was induced by a high-fat and high-sugar diet, while control rats received standard diet and water without sugar for 10 weeks. On 8th-week, Walker-256 tumor cells were inoculated in the rats, and treatment with botryosphaeran (12 mg/Kg b.w.) started. Groups:control tumor-CT, control tumor botryosphaeran-CTB, obese tumor-OT and obese tumor botryosphaeran-OTB. On 10th-week, tumor development, cachexia, metabolic and hematological parameters were analyzed. Tumor development and cachexia were significantly higher in the OT group compared to the CT group, and botryosphaeran attenuated these parameters. OT rats presented accumulation of adipose tissue, reduced muscle mass, glucose intolerance, insulin resistance, hyperglycemia, anemia, leukocytosis, and thrombocytopenia. Botryosphaeran corrected insulin resistance and hyperglycemia, modulated cholesterol levels, and increased leukocyte and lymphocytes in obese rats, which can be attributable to an inflammatory response against the Walker-256 tumor, contributing to a lower tumor development. Our data demonstrated that botryosphaeran was effective in attenuating tumor growth and in improving the metabolic and hematological profiles of the tumor-bearing rats, demonstrating its potential role in the cancer’s management.

Inflammaging? Blame T cells!

Immunometabolism Mitochondrial dysfunction in various tissues is a prominent characteristic of age-related deterioration, but it is unclear how mitochondrial dysfunction in particular cell types contributes to this process. Desdin-Mico et al. generated mice with T cells that were specifically deficient in a mitochondrial DNA–stabilizing protein. These animals exhibited multiple features associated with aging, including neurological, metabolic, muscular, and cardiovascular impairments. The defective T cells initiated an inflammatory program similar to that observed in older animals, a process called “inflammaging.” Blocking the cytokine tumor necrosis factor–α or administering precursors of the cofactor nicotinamide adenine dinucleotide restored many of these symptoms of senescence. These findings may potentially inform future therapies for age-associated diseases, as well as cachexia and cytokine-release syndrome. Science , this issue p. [1371][1] [1]: /lookup/doi/10.1126/science.aax0860

Pathogenetic aspects of cachexia

The relevance of cachexia syndrome is determined by its high prevalence in clinical practice. It accompanies the course of not only oncological diseases, but also the majority of chronic somatic pathologies, such as chronic heart failure, renal failure, diabetes mellitus, chronic obstructive pulmonary disease, acquired immunodeficiency syndrome, rheumatoid arthritis, Alzheimers disease and others. It is known that even a slight weight loss in patients can determine an unfavorable prognosis of the underlying disease and reduce the effectiveness of therapy, and sometimes it becomes the direct cause of death of the patient.&#x0D; Cachexia is a complex metabolic syndrome, which is based on a violation of the central regulation of metabolism. The dangerous combination of decreased appetite (anorexia) and increased metabolism is the result of an imbalance in energy exchange. Treatment of cachexia syndrome is ineffective and limited in means. Given the progressive and irreversible nature of this syndrome, early diagnosis and prevention of its development are the primary task of the doctor.&#x0D; The article describes the main pathogenetic aspects of the development of cachexia syndrome. They can be common in different diseases. The article discusses the difficulties of diagnosing cachexia syndrome, the possibilities and prospects of treatment.

Nutrition in Cancer –Practical Perspective

The syndrome of Cancer cachexia is characterised by an involuntary, sustained loss of weight and skeletal muscle mass, which negatively affects patients’ evolution and their quality of life, increasing the incidence of infection, hospital stay and mortality. The proportion of patients who present weight loss at diagnosis varies between 15 and 40% and may go up to 70 % depending on the type, stage of cancer and disease course. Patients with tumours of the gastrointestinal tract, head and neck, liver and lung cancers are at high risk for malnutrition (de las Peñas R), (Arends).

T cells with dysfunctional mitochondria induce multimorbidity and premature senescence.

The effect of immunometabolism on age-associated diseases remains uncertain. In this work, we show that T cells with dysfunctional mitochondria owing to mitochondrial transcription factor A (TFAM) deficiency act as accelerators of senescence. In mice, these cells instigate multiple aging-related features, including metabolic, cognitive, physical, and cardiovascular alterations, which together result in premature death. T cell metabolic failure induces the accumulation of circulating cytokines, which resembles the chronic inflammation that is characteristic of aging ("inflammaging"). This cytokine storm itself acts as a systemic inducer of senescence. Blocking tumor necrosis factor-α signaling or preventing senescence with nicotinamide adenine dinucleotide precursors partially rescues premature aging in mice with Tfam-deficient T cells. Thus, T cells can regulate organismal fitness and life span, which highlights the importance of tight immunometabolic control in both aging and the onset of age-associated diseases.

Cancer cachexia syndrome in the prediction of outcome in patients with metastatic non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs): Results from a single-institution, prospective, observational study.

e21644 Background: Cancer cachexia syndrome (CCS) is a multifactorial inflammatory syndrome affecting a large subset of patients (pts) with NSCLC which in preclinical models negatively impairs antitumor immunity. We conducted a prospective, observational study to investigate the effect of CCS and sarcopenia on the efficacy of ICIs in NSCLC. Methods: CCS was defined as weight loss of &gt; 5% in the last 6 months or any degree of weight loss &gt; 2% in combination with BMI &lt; 20% or baseline skeletal muscle index at the level of the 3rd lumbar vertebra consistent with sarcopenia. Skeletal muscle index was calculated using slice-o-matic tomovision software in the abdominal CT scan before starting ICIs. Results: 83 pts were included in the analysis. Median follow up was 9.5 months. Median age was 66 years, 61.4% had non-squamous histology, 20.5% received ICIs as first and the remaining as second-line therapy. 20.5% of pts experienced partial response (PR), 31% had stable disease (SD) and 48.2% had disease progression (PD). Median progression-free survival (PFS) was 4.4 months and median overall survival (OS) was 10.33 months. 43.4% of the whole group were categorized as having CCS, whereas 63.3% of 30 pts evaluated using tomovision had sarcopenia. CCS negatively affected response rates (p = 0.003) but not response duration (p = 0.266). CCS was associated with reduced PFS (2.46 vs 5.77 months, p = 0.006) and OS (4.8 vs 14.53 months, p = 0.001). In the multivariate analysis, CCS independently predicted for shorter OS (HR = 2.01; CI: 1,14-3,54; p = 0.014). Sarcopenia was also associated with reduced OS (5.4 vs 17.9 months, p = 0.012). Analysis on the whole pt population will be presented at the conference. Conclusions: CCS is associated with lower response rates and independently predicts for shorter OS in pts with NSCLC treated with ICIs. Further research on CCS could better define its role as a potential biomarker and a research platform for maximizing immunotherapy efficacy.

Tumor development in rats and cancer cachexia are reduced by treatment with botryosphaeran by increasing apoptosis and improving the metabolic profile

AimsCancer is a multifactorial disease characterized by an uncontrolled growth of cells that can lead to cachexia-anorexia syndrome. Botryosphaeran, a fungal (1 → 3)(1 → 6)-β-D-glucan produced by Botryosphaeria rhodina MAMB-05, has presented antimutagenic, antiproliferative, pro-apoptotic, hypoglycemic and hypocholesterolemic effects. This study evaluated the effects of botryosphaeran (30 mg/kg b.w./day) on tumor development and cachexia syndrome in Walker-256 tumor-bearing rats, and also the metabolic and hematological profiles of these animals. Materials and methodsMale Wistar rats were divided into 3 groups: control (C), control tumor (CT) and control tumor botryosphaeran (CTB). On the first day, 1 × 107 Walker-256 tumor cells were inoculated subcutaneously into the right flank of the CT and CTB rats, and concomitantly treatment with botryosphaeran (30 mg/kg b.w./day) started. After the 15th day of treatment, biological parameters, tumor development, cachexia, glucose and lipid profiles, hemogram and protein expression were analyzed. Key findingsBotryosphaeran significantly reduced tumor development (p = 0.0024) and cancer cachexia, modulated the levels of glucose, triglycerides and HDL-cholesterol, and corrected macrocytic anemia. Botryosphaeran also increased significantly the bax expression in the tumor tissue (p = 0.038) demonstrating that this (1 → 3)(1 → 6)-β-D-glucan is increasing the apoptosis of tumor cells. p53, p27, bcl-2, caspase-3 and Forkhead transcription factor 3a (FOXO3a) protein expression were similar among the groups. SignificanceThis study demonstrated that botryosphaeran was effective in decreasing tumor development and cachexia by direct and indirect mechanisms increasing apoptosis and improving the metabolic and hematological profiles.

Ketone Bodies Attenuate Wasting in Models of Atrophy.

BackgroundCancer Anorexia Cachexia Syndrome (CACS) is a distinct atrophy disease negatively influencing multiple aspects of clinical care and patient quality of life. Although it directly causes 20% of all cancer‐related deaths, there are currently no model systems that encompass the entire multifaceted syndrome, nor are there any effective therapeutic treatments.MethodsA novel model of systemic metastasis was evaluated for the comprehensive CACS (metastasis, skeletal muscle and adipose tissue wasting, inflammation, anorexia, anemia, elevated protein breakdown, hypoalbuminemia, and metabolic derangement) in both males and females. Ex vivo skeletal muscle analysis was utilized to determine ubiquitin proteasome degradation pathway activation. A novel ketone diester (R/S 1,3‐Butanediol Acetoacetate Diester) was assessed in multifaceted catabolic environments to determine anti‐atrophy efficacy.ResultsHere, we show that the VM‐M3 mouse model of systemic metastasis demonstrates a novel, immunocompetent, logistically feasible, repeatable phenotype with progressive tumor growth, spontaneous metastatic spread, and the full multifaceted CACS with sex dimorphisms across tissue wasting. We also demonstrate that the ubiquitin proteasome degradation pathway was significantly upregulated in association with reduced insulin‐like growth factor‐1/insulin and increased FOXO3a activation, but not tumor necrosis factor‐α‐induced nuclear factor‐kappa B activation, driving skeletal muscle atrophy. Additionally, we show that R/S 1,3‐Butanediol Acetoacetate Diester administration shifted systemic metabolism, attenuated tumor burden indices, reduced atrophy/catabolism and mitigated comorbid symptoms in both CACS and cancer‐independent atrophy environments.ConclusionsOur findings suggest the ketone diester attenuates multifactorial CACS skeletal muscle atrophy and inflammation‐induced catabolism, demonstrating anti‐catabolic effects of ketone bodies in multifactorial atrophy.

Ketone Bodies Attenuate Wasting in Diverse Models of Atrophy

BackgroundCancer anorexia cachexia syndrome (CACS) is a distinct atrophy disease negatively influencing multiple aspects of clinical care and patient quality of life. Although it directly causes 20% of all cancer‐related deaths, there are currently no model systems that encompass the entire multifaceted syndrome, nor are there any effective therapeutic treatments.MethodsA novel model of systemic metastasis was evaluated for the comprehensive CACS (metastasis, skeletal muscle and adipose tissue wasting, inflammation, anorexia, anemia, elevated protein breakdown, hypoalbuminemia, and metabolic derangement) in both males and females. Ex vivo skeletal muscle analysis was utilized to determine ubiquitin proteasome degradation pathway activation. A novel ketone diester (R/S 1,3‐butanediol acetoacetate diester) was assessed in multifaceted catabolic environments to determine anti‐atrophy efficacy.ResultsHere, we show that the VM‐M3 mouse model of systemic metastasis demonstrates a novel, immunocompetent, logistically feasible, repeatable phenotype with progressive tumor growth, spontaneous metastatic spread, and the full multifaceted CACS with sex dimorphisms across tissue wasting. We also demonstrate that the ubiquitin proteasome degradation pathway was significantly upregulated in association with reduced IGF‐1/insulin and increased FOXO3a activation, but not TNF‐α‐induced NF‐κB activation, driving skeletal muscle atrophy. Additionally, we show that R/S 1,3‐butanediol acetoacetate diester administration shifted systemic metabolism, attenuated tumor burden indices, reduced tissue catabolism, and mitigated comorbid symptoms in both CACS and cancer‐independent atrophy environments.ConclusionsOur findings suggest the ketone diester attenuates multifactorial CACS skeletal muscle atrophy and inflammation‐induced tissue catabolism, demonstrating anti‐catabolic effects of ketones bodies in multifactorial atrophy.Support or Funding InformationThis work was supported by Disruptive Nutrition (Grant #: 61431150), Florida High Tech Corridor (Grant #: FHT 18‐15), Donner Foundation (Grant #: 61431151), and Office of Naval Research (Grant #: N00014‐18‐1‐2701). Additional funding for muscle molecular analysis were provided by discretionary laboratory funds of MDR.

The evolution of zebrafish RAG2 protein is required for adapting to the elevated body temperature of the higher endothermic vertebrates

The recombination activating gene (RAG or RAG1/RAG2 complex)-mediated adaptive immune system is a hallmark of jawed vertebrates. It has been reported that RAG originated in invertebrates. However, whether RAG further evolved once it arose in jawed vertebrates remains largely unknown. Here, we found that zebrafish RAG (zRAG) had a lower activity than mouse RAG (mRAG). Intriguingly, the attenuated stability of zebrafish RAG2 (zRAG2), but not zebrafish RAG1, caused the reduced V(D)J recombination efficiency compared to mRAG at 37 °C which are the body temperature of most endotherms except birds. Importantly, the lower temperature 28 °C, which is the best temperature for zebrafish growth, made the recombination efficiency of zRAG similar to that of mRAG by improving the stability of zRAG2. Consistent with the prementioned observation, the V(D)J recombination of Rag2KI/KI mice, which zRAG2 was substituted for mRAG2, was also severely impaired. Unexpectedly, Rag2KI/KI mice developed cachexia syndromes accompanied by premature death. Taken together, our findings illustrate that the evolution of zebrafish RAG2 protein is required for adapting to the elevated body temperature of the higher endothermic vertebrates.

Brown Adipose Tissue, Thermogenesis, and Obesity: A Review of Literature

The white adipose tissue (WAT) mass in adult humans ranges between 10-35 kg. The cells are normally sensitive to insulin in the fed state, and to glucagon and adrenaline in fasting or during exercise. Well-fed sedentary individuals are prone to weight gain as they fall victims to the anabolic mechanisms led mainly by insulin. Brown adipose tissue (BAT), by contrast, stores smaller amounts of triglycerides in multi-locular droplets, is highly vascularized and its cells are rich in unique mitochondria which are capable of uncoupling oxidation from phosphorylation or ATP formation. The tissue is innerved by the sympathetic nervous system and is highly sensitive to iodothyronines. It releases heat in the body in response to sympathetic activity. BAT unique mitochondria express numerous cristae and, unlike ordinary mitochondria on other body cells including WAT cells, they express uncoupling protein-1 (UCP-1, or thermogenin). UCP-1 allows the mitochondria to oxidize more fat and glucose as they escape the controlling mechanisms that depend on the coupling of oxidation to the demand for ATP, i.e., uncouples oxidative phosphorylation. Thermogenin (UCP-1) is a natural un-coupler of oxidative phosphorylation as it dissipates the proton gradient generated across the inner mitochondrial membrane, which is required to attain a certain level for the activation of ATP synthesis in mitochondrial matrix. In BAT, ATP synthesis is inhibited, as the protons are dissipated, and most energy is released as heat. The different proportions and activity of BAT and WAT in different individuals might explain why some people are more prone to weight gain, and find it difficult to lose weight, than others; and also explains the tendency for weight gain as individuals get older. New approaches in the battle against obesity, metabolic syndrome and type 2 diabetes mellitus are expected through better understanding of how this balance between WAT and BAT is controlled. Interestingly, long term adrenergic stimulation of WAT induces browning of some white adipocytes, and the tissue gradually turns into &amp; quot; beige &amp; quot; adipose tissue, which shares characteristics of brown adipose tissue like thermogenesis, larger number of mitochondria and smaller lipid droplets, all developing in a gradual way. The adipose tissue interconverts its cell types in order to adapt for the changing metabolic balance and other stimuli. This phenomenon is currently incompletely understood, albeit significant for our understanding of obesity, metabolic syndrome and type 2 diabetes mellitus and many consequent complications of insulin resistance. Moreover, the nervous system is involved in the regulation of WAT and BAT through effects on fat cell proliferation, differentiation, trans-differentiation and apoptosis. The brain interacts with different adipocytes and adipokines in the pathogenesis of obesity, type 2 diabetes mellitus, anorexia, cachexia and other syndromes. This review will target many of these aspects in an attempt to draw more attention in the direction of this major health issue.