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Simple Summary: Cancer patients frequently develop a syndrome named cachexia that causes severe muscle loss and frailty, eventually representing the cause of death. Muscle atrophy and muscle weakness are characterized by massive degradation of endogenous proteins, potentially consequent to excessive disposal of mitochondria through the selective autophagic process of mitophagy. This study explored whether selectively silencing BNIP3, a mitophagy-related protein upregulated in the muscle of both mouse and human cancer hosts, could help in preventing muscle loss. Two distinct methodological silencing approaches were tested, either by electroporation of a plasmid or via adenoviral particle injection. Although the first method was ineffective in tumor-bearing mice, the adenovirus-based approach significantly reduced BNIP3 levels and moderately increased muscle fiber size, suggesting partial prevention of muscle atrophy. BNIP3 silencing also maintained mitochondrial mass without disrupting oxidative balance, highlighting BNIP3's central role in cancer cachexia and suggesting that targeting BNIP3 may help in supporting muscle health in cancer patients. Background and Aims: Cancer cachexia is a complex syndrome affecting most cancer patients and is directly responsible for about 20% of cancer-related deaths. Previous studies showed muscle proteolysis hyper-activation and mitophagy induction in tumor-bearing animals. While basal mitophagy is required for maintaining muscle mass and quality, excessive mitophagy promotes uncontrolled protein degradation, muscle loss and impaired function. BNIP3, a key mitophagy-related protein, is significantly increased in the muscles of both mice and human cancer hosts. This study aimed to define the potential of mitigating mitophagy via BNIP3 downregulation in preserving mitochondrial integrity, counteracting skeletal muscle loss in experimental cancer cachexia. Methods: Two in vivo gene delivery methods were performed to knock down muscle BNIP3: electroporation of a BNIP3-specific shRNA expression vector or adenovirus injection. Results: The electroporation effectively reduced muscle BNIP3 in healthy mice but was ineffective in C26 tumor-bearing mice. In contrast, adenovirus-mediated BNIP3 knockdown successfully decreased BNIP3 levels also in tumor hosts. Although BNIP3 knockdown did not impact overall on body or muscle mass, it improved muscle fiber size in C26-bearing miceh2, suggesting partial prevention of muscle atrophy. Mitochondrial respiratory chain complexes (OxPhos) and TOM20 protein levels were consistently rescued, indicating improvements in mitochondrial mass, while H2O2 levels were unchanged among the groups, suggesting that BNIP3 downregulation does not impair the endogenous control of oxidative balance. Conclusions: These findings suggest that a fine balance between mitochondrial disposal and biogenesis is fundamental for preserving muscle homeostasis and highlight a potential role for BNIP3 modulation against cancer-induced muscle wasting. [ABSTRACT FROM AUTHOR]

Background/Objectives: Cancer cachexia is a multifactorial syndrome characterized by the progressive loss of skeletal muscle mass and adipose tissue. Dalbergia odorifer is widely used in traditional medicine in Korea and China to treat various diseases. However, its exact role and underlying mechanism in regulating cancer cachexia have not been elucidated yet. This research was conducted to investigate the effect of D. odorifer extract (DOE) in preventing the development of cancer-induced cachexia symptoms and figure out the relevant mechanisms. Methods: A cancer cachexia model was established in Balb/c mice using the CT26 colon carcinoma cell line. To evaluate the anti-cachexia effect of Dalbergia odorifer extract (DOE), CT26-bearing mice were orally administered with DOE at concentrations of 50 and 100 mg/kg BW for 14 days. C2C12 myotubes and 3T3L1 adipocytes were treated with 80% CT26 conditioned medium, DOE, and wortmannin, a particular AKT inhibitor to determine the influence of DOE in the AKT signaling pathway. Mice body weight, food intake, myofiber cross-sectional area, adipocyte size, myotube diameter, lipid accumulation, and relevant gene expression were analyzed. Results: The oral administration of DOE at doses of 50 and 100 mg/kg body weight to CT26 tumor-bearing mice resulted in a significant reduction in body weight loss, an increase in food intake, and a decrease in serum glycerol levels. Furthermore, DOE treatment led to an increase in muscle mass, larger muscle fiber diameter, and elevated expression levels of MyH2 and Igf1, while simultaneously reducing the expression of Atrogin1 and MuRF1. DOE also attenuated adipose tissue wasting, as evidenced by increased epididymal fat mass, enlarged adipocyte size, and upregulated Pparγ expression, alongside a reduction in Ucp1 and IL6 levels. In cachectic C2C12 myotubes and 3T3-L1 adipocytes induced by the CT26 conditioned medium, DOE significantly inhibited muscle wasting and lipolysis by activating the AKT signaling pathway. The treatment of wortmannin, a specific AKT inhibitor, effectively neutralized DOE's impact on the AKT pathway, myotube diameter, and lipid accumulation. Conclusions: DOE ameliorates cancer cachexia through the expression of genes involved in protein synthesis and lipogenesis, while suppressing those related to protein degradation, suggesting its potential as a plant-derived therapeutic agent in combating cancer cachexia. [ABSTRACT FROM AUTHOR]

Pharmacists' roles in cachexia care are unclear. This study aimed to clarify the knowledge and practice of cachexia care and identify factors related to the practice of cachexia care among pharmacists. Information on the knowledge and practice of cachexia care was obtained. Components of practicing multimodal care were evaluated. Participants were categorized into two groups according to practicing multimodal care levels. Comparisons were made between the groups, and multiple regression analysis was employed. Of the 451 pharmacists, 243 responded. They were categorized into the Practicing group (n = 119) and Not practicing group (n = 124). Significant differences were observed for the number of advanced cancer patients/month, frequency of caring for them, and involvement in training programs on cachexia. The Practicing group had significantly better knowledge about cachexia. The Practicing group used guidelines, items, and symptoms more frequently to detect cachexia. The Practicing group tended to detect cachexia and initiate interventions in earlier phases and in patients with a better status. Multivariate logistic regression analysis showed that the most significant factor was the regular provision of care (odds ratio, 2.07; 95% confidence interval, 1.10–3.92). The regular provision of care was associated with the practice of multimodal care. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer cachexia is a complex metabolic condition that is often overlooked and recognized in a late irreversible phase. There is a continuing effort to discover and define a biochemical biomarker of the condition. In this study, we have chosen interleukin-13 (IL-13) and transforming growth factor beta (TGF-β), i.e., two cytokines with presumed roles in the development of cancer cachexia, and we measured their concentrations in the serum and saliva of cachectic patients with metastatic solid tumors, non-cachectic patients with metastatic solid tumors, and healthy individuals. We have demonstrated the role of saliva cytokine measurement as a potential sample for cachexia investigations as opposed to the standard approach to biomarker research, which is serum measurement. We have also found that the salivary IL-13 and TGF-ß are independent risk factors and thus could serve as potential biomarkers of the condition, a fact that warrants further research and confirmation. Cancer cachexia is a syndrome characterized by weight and muscle loss and functional impairment, strongly influencing survival in cancer patients. In this study, we aimed to establish the role of saliva cytokine measurement in cancer cachexia investigation and define two potential independent salivary biomarkers of the condition. Methods: serum and saliva specimens were obtained from 78 patients. Forty-six patients were non-cachectic, and 32 patients were cachectic (per SCRINIO group criteria), all with metastatic solid tumors. Commercial ELISA kits were used to determine the salivary and serum concentrations of interleukin 13 (IL-13) and transforming growth factor beta (TGF-β) in two patient groups and healthy controls. Laboratory values were obtained from the hospital information system, and weight and height were measured at the time of sampling. Results: A statistically significant difference was observed between the groups in saliva IL-13 concentrations but no difference in serum concentrations. Statistically significant differences were also observed between the groups in saliva and serum concentrations of TGF-β. Logistic regression analysis has identified salivary IL-13 and TGF-β as independent factors for cancer cachexia. Conclusions: We demonstrated saliva as a valuable specimen for cachexia investigation and established IL-13 and TGF-β as potential cancer cachexia biomarkers. Further research is needed to evaluate these findings. [ABSTRACT FROM AUTHOR]

Cancer cachexia (CC) continues to challenge clinicians by massively impairing patients' prognosis, mobility, and quality of life through skeletal muscle wasting. CC also includes cardiac cachexia as characterized by atrophy, compromised metabolism, innervation and function of the myocardium through factors awaiting clarification for therapeutic targeting. Because monoamine oxidase-A (MAO-A) is a myocardial source of H2O2 and implicated in myofibrillar protein catabolism and heart failure, we presently studied myocardial MAO-A expression, inflammatory cells, and capillarization together with transcripts of pro-inflammatory, -angiogenic, -apoptotic, and -proteolytic signals (by qRT-PCR) in a 3x-transgenic (LSL-KrasG12D/+; LSL-TrP53R172H/+; Pdx1-Cre) mouse model of orthotopic pancreatic ductal adenoarcinoma (PDAC) compared to wild-type (WT) mice. Moreover, we evaluated the effect of MAO-A inhibition by application of harmine hydrochloride (HH, 8 weeks, i.p., no sham control) on PDAC-related myocardial alterations. Myocardial MAO-A protein content was significantly increased (1.69-fold) in PDAC compared to WT mice. PDAC was associated with an increased percentage of atrogin-1+ (p < 0.001), IL-1β+ (p < 0.01), COX2+ (p < 0.001), and CD68+ (p > 0.05) cells and enhanced transcripts of pro-inflammatory IL-1β (2.47-fold), COX2 (1.53-fold), TNF (1.87-fold), and SOCS3 (1.64-fold). Moreover, PDAC was associated with a reduction in capillary density (−17%, p < 0.05) and transcripts of KDR (0.46-fold) but not of VEGFA, Notch1, or Notch3. Importantly, HH treatment largely reversed the PDAC-related increases in atrogin-1+, IL-1β+, and TNF+ cell fraction as well as in COX2, IL-1β, TNF, and SOCS3 transcripts, whereas capillary density and KDR transcripts failed to improve. In mice with PDAC, increased myocardial pro-atrophic/-inflammatory signals are attributable to increased expression of MAO-A, because they are significantly improved with MAO-A inhibition as a potential novel therapeutic option. The PDAC-related loss in myocardial capillary density may be due to other mechanisms awaiting evaluation with consideration of cardiomyocyte size, cardiac function and physical activity. [ABSTRACT FROM AUTHOR]

The experience of bearing witness to the lack of appetite and involuntary weight loss that characterizes cancer anorexia–cachexia syndrome (CACS) is reported to be stressful for family members. Research identifies that family members engage in a wide range of behaviors in response to a relative who shows minimal interest in eating and is literally 'wasting away' before their eyes. Some families, though concerned about the symptoms of CACS, do not dwell excessively on the patient's nutritional intake while others continually harass the patient to eat and petition health care providers for aggressive nutritional interventions to eat in an attempt to stave off further physical deterioration. While studies have detailed how family members respond to a terminally ill relative with CACS, empirical work explicating the explanatory models of CACS that they hold is lacking. Explanatory models (EMs) reflect the beliefs and ideas that families have about why illness and symptoms occur, the extent to which they can be controlled, how they should be treated, and how interventions should be evaluated. To address this gap in the literature, a grounded theory study guided by Kleinman's Explanatory Model questions was conducted with 25 family members of advanced cancer patients. The core category of 'Wayfaring' integrates the key categories of the model and maps onto Kleinman's questions about CACS onset, etiology, natural course, physiological processes/anatomical structures involved, treatment, and the impacts of disease on patient and family. Findings suggest that a divergence between some biomedical constructions of CACS and explanatory models held by family members may fuel the family–health care provider conflict, thereby providing direction for communication with families about care of the patient with anorexia–cachexia. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer cachexia (CC) is a syndrome affecting advanced cancer patients, causing inflammation, metabolic dysfunction, and a decline in quality of life. It increases the risk of mortality. Nutritional therapies are being tested for improving muscle metabolism in cancer patients, but no special therapies have been validated in clinical practice. Studies suggest increasing muscle protein synthesis through amino acids or protein intake, and physical activity can reduce muscle atrophy. This manuscript provides an overview of the preclinical and clinical approaches for the use of amino acids with and without exercise therapy to improve muscle metabolism in cachexia. Cancer cachexia is a multifaceted syndrome that impacts individuals with advanced cancer. It causes numerous pathological changes in cancer patients, such as inflammation and metabolic dysfunction, which further diminish their quality of life. Unfortunately, cancer cachexia also increases the risk of mortality in affected individuals, making it an important area of focus for cancer research and treatment. Several potential nutritional therapies are being tested in preclinical and clinical models for their efficacy in improving muscle metabolism in cancer patients. Despite promising results, no special nutritional therapies have yet been validated in clinical practice. Multiple studies provide evidence of the benefits of increasing muscle protein synthesis through an increased intake of amino acids or protein. There is also increasing evidence that exercise can reduce muscle atrophy by modulating protein synthesis. Therefore, the combination of protein intake and exercise may be more effective in improving cancer cachexia. This review provides an overview of the preclinical and clinical approaches for the use of amino acids with and without exercise therapy to improve muscle metabolism in cachexia. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer cachexia (CC) is a complex syndrome requiring a multimodal approach. Although a universally accepted definition and staging criteria for cancer cachexia remains elusive, there is general consensus regarding the importance of elements such as weight loss, muscle wasting, and poor appetite. Epidemic trends of obesity and overlapping conditions such as sarcopenia and frailty further complicate CC definition, staging, and relevant outcome measures. Despite progress in understanding the molecular mechanisms of CC, there is no single, consistently effective pharmacotherapy for CC and, unsurprisingly, there are variations among guidelines regarding management. Current pharmacologic research is focused on promising targeted treatments; however, a multimodal approach is likely to be more effective than any single therapeutic agent. This narrative review provides an update on non-pharmacologic and pharmacologic treatment and proposes a theoretical model for management of CC, which includes a multimodal therapeutic approach directed at the various mechanisms contributing to CC. Despite a better understanding of the mechanisms causing cancer cachexia (CC) and development of promising pharmacologic and supportive care interventions, CC persists as an underdiagnosed and undertreated condition. CC contributes to fatigue, poor quality of life, functional impairment, increases treatment related toxicity, and reduces survival. The core elements of CC such as weight loss and poor appetite should be identified early. Currently, addressing contributing conditions (hypothyroidism, hypogonadism, and adrenal insufficiency), managing nutrition impact symptoms leading to decreased oral intake (nausea, constipation, dysgeusia, stomatitis, mucositis, pain, fatigue, depressed mood, or anxiety), and the addition of pharmacologic agents when appropriate (progesterone analog, corticosteroids, and olanzapine) is recommended. In Japan, the clinical practice has changed based on the availability of Anamorelin, a ghrelin receptor agonist that improved lean body mass, weight, and appetite-related quality of life (QoL) compared to a placebo, in phase III trials. Other promising therapeutic agents currently in trials include Espindolol, a non-selective β blocker and a monoclonal antibody to GDF-15. In the future, a single therapeutic agent or perhaps multiple medications targeting the various mechanisms of CC may prove to be an effective strategy. Ideally, these medications should be incorporated into a multimodal interdisciplinary approach that includes exercise and nutrition. [ABSTRACT FROM AUTHOR]

Background: Nutritional deficiencies are frequently observed in patients with head and neck cancer (HNC) undergoing radiation therapy. microRNAs (miRNAs) were found to play an important role in the development of metabolic disorders throughout regulation of genes involved in inflammatory responses. This study aimed to explore the correlation between pre-treatment miR-5682 expression and parameters reflecting nutritional deficits in laryngeal cancer (LC) patients subjected to radiotherapy (RT). Methods: Expression of miR-5682 was analyzed in plasma samples of 56 male LC individuals. Nutritional status of LC patients was assessed using anthropometric and laboratory parameters, bioelectrical impedance analysis (BIA) and clinical questionnaires. Results: A high expression of miR-5682 was associated with significantly lower values of BMI, fat mass, fat-free mass and plasma albumin at selected periods of RT course. miR-5682 allowed us to distinguish between patients classified with both SGA-C and low albumin level from other LC patients with 100% sensitivity and 69.6% specificity (AUC = 0.820; p < 0.0001). Higher expression of studied miRNA was significantly associated with shorter median overall survival (OS) in LC patients (HR = 2.26; p = 0.008). Conclusions: analysis of miR-5682 expression demonstrates a potential clinical utility in selection of LC patients suffering from nutritional deficiencies developing as a consequence of RT-based therapy. [ABSTRACT FROM AUTHOR]

Cardiac disorders in cancer patients pose significant challenges to disease prognosis. While it has been established that these disorders are linked to cancer cells, the precise underlying mechanisms remain elusive. In this study, we investigated the impact of cancerous ascites from the rat colonic carcinoma cell line RCN9 on H9c2 cardiomyoblast cells. We found that the ascites reduced mitochondrial volume, increased oxidative stress, and decreased membrane potential in the cardiomyoblast cells, leading to apoptosis and autophagy. Although the ascites fluid contained a substantial amount of high-mobility group box-1 (HMGB1), we observed that neutralizing HMGB1 with a specific antibody mitigated the damage inflicted on myocardial cells. Our mechanistic investigations revealed that HMGB1 activated both nuclear factor κB and phosphoinositide 3-kinases-AKT signals through HMGB1 receptors, namely the receptor for advanced glycation end products and toll-like receptor-4, thereby promoting apoptosis and autophagy. In contrast, treatment with berberine (BBR) induced the expression of miR-181c-5p and miR-340-5p while suppressing HMGB1 expression in RCN9 cells. Furthermore, BBR reduced HMGB1 receptor expression in cardiomyocytes, consequently mitigating HMGB1-induced damage. We validated the myocardial protective effects of BBR in a cachectic rat model. These findings underscore the strong association between HMGB1 and cancer cachexia, highlighting BBR as a promising therapeutic agent for myocardial protection through HMGB1 suppression and modulation of the signaling system. [ABSTRACT FROM AUTHOR]

Simple Summary: Our study examined how muscle function is affected in cancer patients, particularly those at risk of developing muscle wasting (cachexia). We tested a combination of mild exercise and a protein-rich diet as a potential preventive measure. By analysing muscle fibres from patients undergoing different treatments, we found that cancer cachexia leads to muscle weakness and stiffness. However, our results show that the combined therapy helps maintain muscle flexibility and function. This suggests that such an intervention could improve the quality of life for cancer patients by preserving muscle health. Patients with aggressive cancer, e.g., gastrointestinal cancer, are prone (≥50% chance) to developing cancer cachexia (CC). Little is known about the effects of CC on the biomechanical function of muscle. A promising prevention strategy was found in the form of a multi-modal therapy combining mild resistance exercise (e.g., whole-body electro-myostimulation, WB-EMS) and a protein-rich diet. In a previous study of ours, this was effective in counteracting the loss of muscle mass, yet a systematic and comprehensive assessment of active and passive single muscle fibre functions was so far absent. This pilot study investigated the biomechanical function of single muscle fibres (rectus abdominis) from the biopsies of conventionally treated (pre-)cachectic cancer ((pre-)CC) patients (m = 9), those receiving the multi-modal therapy comprising WB-EMS training and protein-rich nutrition (m = 3), and a control group (m = 5). Our findings not only align with previous findings showing the absolute force loss in CC that is accelerated by atrophy but also speak in favour of a different, potentially energy- and Ca2+-homeostasis-related effect that compromises muscle contraction (F ~0.9 mN vs. F ~0.6 mN in control patients). However, myofibrillar Ca2+ sensitivity and the quality of contraction were unaltered (pCa50: 5.6–5.8). Single fibres from the (pre-)CC patients receiving WB-EMS training and protein supplementation were significantly more compliant (p < 0.001 at ≥130% of resting length L0). Those fibres displayed a similar softness to the ones from the control patients (axial compliance ~15 m/N at ≥130% L0), while single fibres from the patients with (developing) cachexia were significantly stiffer (axial compliance ~7 m/N, p < 0.001 at ≥130% L0). Adjuvant multi-modal therapy (WB-EMS training and nutritional support) contributes to maintaining the axial compliance of single fibres and potentially improves the quality of life for patients at risk of developing CC. [ABSTRACT FROM AUTHOR]

Simple Summary: Symptom management in the cancer setting focuses on the improvement of the overall quality of life and physical function, particularly for patients with muscle and weight loss, a syndrome known as cachexia, who suffer from low functional ability. Yet, there are no guidelines for measuring or defining low functional ability or standards for identifying meaningful changes in functional ability in response to disease and/or treatment. This unmet need is a major obstacle to developing new/improved therapies for cancer cachexia. This review presents the available evidence for identifying low functional ability and meaningful changes in functional ability in patients with cancer cachexia. Patients with cachexia may display a meaningful reduction in hand grip strength, which may be improved by interventions aiming to increase muscle mass. Future studies should confirm these observations in addition to identifying low functional ability and meaningful changes for other functional outcomes. Managing clinical manifestations of cancer/treatment burden on functional status and quality of life remains paramount across the cancer trajectory, particularly for patients with cachexia who display reduced functional capacity. However, clinically relevant criteria for classifying functional impairment at a single point in time or for classifying meaningful functional changes subsequent to disease and/or treatment progression are lacking. This unmet clinical need remains a major obstacle to the development of therapies for cancer cachexia. This review aims to describe current literature-based evidence for clinically meaningful criteria for (1) functional impairment at a single timepoint between cancer patients with or without cachexia and (2) changes in physical function over time across interventional studies conducted in patients with cancer cachexia. The most common functional assessment in cross-sectional and interventional studies was hand grip strength (HGS). We observed suggestive evidence that an HGS deficit between 3 and 6 kg in cancer cachexia may display clinical relevance. In interventional studies, we observed that long-duration multimodal therapies with a focus on skeletal muscle may benefit HGS in patients with considerable weight loss. Future studies should derive cohort-specific clinically relevant criteria to confirm these observations in addition to other functional outcomes and investigate appropriate patient-reported anchors. [ABSTRACT FROM AUTHOR]

Simple Summary: According to the literature, 35–71% of multiple myeloma patients have nutritional disorders. In the development of cachexia and malnutrition, the inflammatory process, accompanied by an increase in the level of proinflammatory cytokines, plays a key role. Interleukin-1β is a cytokine that plays an important role in the mechanisms responsible for muscle and adipose tissue breakdown during malnutrition and cachexia. This study aimed to investigate the association of IL1B gene polymorphism and interleukin-1β plasma concentration with the occurrence of nutritional disorders and survival in patients with multiple myeloma. The presence of the CC genotype of the IL1B gene was associated with a higher plasma concentration of interleukin-1β, a higher risk of cachexia, and poor prognosis. Determination of IL1B polymorphism may be a useful predictive marker of the risk of cachexia and prognostic factor in multiple myeloma patients. Background: Multiple myeloma (MM) is a hematological neoplasm of the early precursor of B-cells. The most characteristic symptoms observed during MM include hypocalcemia, anemia, bacterial infections, and renal damage. Nutritional disorders, especially malnutrition, are noted in about 35–71% of MM patients. Interleukin 1 beta (IL-1β) is a proinflammatory cytokine responsible for muscle atrophy and lipolysis during malnutrition and cachexia. This study aimed to evaluate the usefulness of the IL1B single-nucleotide polymorphism (SNP) (rs1143634) and plasma concentration of IL-1β in the assessment of the risk of nutritional disorders and prognosis in patients with MM. Methods: In our study, 93 patients with the de novo MM were enrolled. The real-time PCR with specific TaqMan probes method was used in genotyping. The IL-1β ELISA kit was used to determine IL-1β concentration in plasma samples. Results: Patients with the CC genotype, compared to the carriers of the other variants of the IL1B, demonstrated significantly higher concentrations of IL-1β in plasma (7.56 vs. 4.97 pg/mL), a significantly higher risk of cachexia (OR = 5.11), and a significantly higher risk of death (HR = 2.03). Moreover, high IL-1β plasma level was related to a significantly higher risk of cachexia (OR = 7.76); however, it was not significantly associated with progression-free survival (PFS) or overall survival (OS). Conclusions: Determination of the IL1B SNP (rs1143634) and plasma concentration of IL-1β may be useful in the assessment of the risk of cachexia and prognosis in patients with MM. [ABSTRACT FROM AUTHOR]

Simple Summary: Currently, muscle testing remains underutilized in cancer cachexia research, since muscle biopsies are mainly performed at the end of experimental protocols. We aimed to introduce the concept of longitudinal muscle testing for cancer cachexia by initially demonstrating its feasibility and safety for the test subjects. Following that, we tested the hypothesis on a tumor-bearing rat model. Results were indicative of heterogeneity in cancer cachexia manifestation between different subjects and throughout the disease course. There is an abundance of researched pathways and mechanisms of cachexia, as well as interventions to target them. Thus, moving forward, developing biomarkers to suggest "what to target and when to do it" is essential. Sequential muscle biopsies can serve as a promising tool to guide personalized precision treatment for cancer cachexia, as well as to monitor the disease evolution and response to therapy. In the rapidly evolving landscape of cancer cachexia research, the development and refinement of diagnostic and predictive biomarkers constitute an ongoing challenge. This study aims to introduce longitudinal muscle biopsies as a potential framework for disease monitoring and treatment. The initial feasibility and safety assessment was performed for healthy mice and rats that received two consecutive muscle biopsies. The assessment was performed by utilizing three different tools. Subsequently, the protocol was also applied in leiomyosarcoma tumor-bearing rats. Longitudinal muscle biopsies proved to be a safe and feasible technique, especially in rat models. The application of this protocol to tumor-bearing rats further affirmed its tolerability and feasibility, while microscopic evaluation of the biopsies demonstrated varying levels of muscle atrophy with or without leukocyte infiltration. In this tumor model, sequential muscle biopsies confirmed the variability of the cancer cachexia evolution among subjects and at different time-points. Despite the abundance of promising cancer cachexia data during the past decade, the full potential of muscle biopsies is not being leveraged. Sequential muscle biopsies throughout the disease course represent a feasible and safe tool that can be utilized to guide precision treatment and monitor the response in cancer cachexia research. [ABSTRACT FROM AUTHOR]

Cachexia is a condition characterized by substantial loss of body weight resulting from the depletion of skeletal muscle and adipose tissue. A considerable fraction of patients with advanced cancer, particularly those who have been diagnosed with pancreatic or gastric cancer, lung cancer, prostate cancer, colon cancer, breast cancer, or leukemias, are impacted by this condition. This syndrome manifests at all stages of cancer and is associated with an unfavorable prognosis. It heightens the susceptibility to surgical complications, chemotherapy toxicity, functional impairments, breathing difficulties, and fatigue. The early detection of patients with cancer cachexia has the potential to enhance both their quality of life and overall survival rates. Regarding this matter, blood biomarkers, although helpful, possess certain limitations and do not exhibit universal application. Additionally, the available treatment options for cachexia are currently limited, and there is a lack of comprehensive understanding of the underlying molecular pathways associated with this condition. Thus, this review aims to provide an overview of molecular mechanisms associated with cachexia and potential therapeutic targets for the development of effective treatments for this devastating condition. [ABSTRACT FROM AUTHOR]

Skeletal muscle regeneration is a complex process involving the generation of new myofibers after trauma, competitive physical activity, or disease. In this context, adult skeletal muscle stem cells, also known as satellite cells (SCs), play a crucial role in regulating muscle tissue homeostasis and activating regeneration. Alterations in their number or function have been associated with various pathological conditions. The main factors involved in the dysregulation of SCs' activity are inflammation, oxidative stress, and fibrosis. This review critically summarizes the current knowledge on the role of SCs in skeletal muscle regeneration. It examines the changes in the activity of SCs in three of the most common and severe muscle disorders: sarcopenia, muscular dystrophy, and cancer cachexia. Understanding the molecular mechanisms involved in their dysregulations is essential for improving current treatments, such as exercise, and developing personalized approaches to reactivate SCs. [ABSTRACT FROM AUTHOR]

Cachexia is a devastating pathology that worsens the quality of life and antineoplastic treatment outcomes of oncologic patients. Herein, we report that the secretome from murine colon carcinoma CT26 induces cachectic features in both murine and human adipocytes that are associated with metabolic alterations such as enhanced lactate production and decreased oxygen consumption. The use of oxamate, which inhibits lactate dehydrogenase activity, hinders the effects induced by CT26 secretome. Interestingly, the CT26 secretome elicits an increased level of lactate dehydrogenase and decreased expression of adiponectin. These modifications are driven by the STAT3 signalling cascade since the inhibition of STAT3 with WP1066 impedes the formation of the cachectic condition and the alteration of lactate dehydrogenase and adiponectin levels. Collectively, these findings show that STAT3 is responsible for the altered lactate dehydrogenase and adiponectin levels that, in turn, could participate in the worsening of this pathology and highlight a step forward in the comprehension of the mechanisms underlying the onset of the cachectic condition in adipocytes. [ABSTRACT FROM AUTHOR]

Cancer cachexia is a complex malnutrition syndrome that causes progressive dysfunction. This syndrome is accompanied by protein and energy losses caused by reduced nutrient intake and the development of metabolic disorders. As many as 80% of patients with advanced cancer develop cancer cachexia; however, an effective targeted treatment remains to be developed. In this study, we developed a novel rat model that mimics the human pathology during cancer cachexia to elucidate the mechanism underlying the onset and progression of this syndrome. We subcutaneously transplanted rats with SLC cells, a rat lung adenocarcinoma cell line, and evaluated the rats' pathophysiological characteristics. To ensure that our observations were not attributable to simple starvation, we evaluated the characteristics under tube feeding. We observed that SLC-transplanted rats exhibited severe anorexia, weight loss, muscle atrophy, and weakness. Furthermore, they showed obvious signs of cachexia, such as anemia, inflammation, and low serum albumin. The rats also exhibited weight and muscle losses despite sufficient nutrition delivered by tube feeding. Our novel cancer cachexia rat model is a promising tool to elucidate the pathogenesis of cancer cachexia and to conduct further research on the development of treatments and supportive care for patients with this disease. [ABSTRACT FROM AUTHOR]

Simple Summary: Muscle and fat losses during chemotherapy for advanced pancreatic cancer are highly prevalent and associated with tumour progression during treatment. Whether chemotherapy treatment also drives these losses is unknown. This retrospective study aimed to define the effects of chemotherapy and tumour progression on muscle and fat loss and determine the relevance of these losses to overall survival. In a cohort of 210 patients over a standardised scan interval, we demonstrated that tumour progression was associated with greater loss of each tissue compared to tumour control. Furthermore, fluorouracil-based triplet chemotherapy was associated with more muscle loss, while gemcitabine-based doublet chemotherapy was associated with more fat loss. Independent of tumour response, patients with the most muscle or fat loss by tertiles had 72–73% greater hazard of death compared to those with the smallest losses. Muscle and adipose losses are adverse effects of chemotherapy treatment that require targeted management strategies. Muscle and adipose wasting during chemotherapy for advanced pancreatic cancer (aPC) are associated with poor outcomes. We aimed to quantify the contributions of chemotherapy regimen and tumour progression to muscle and adipose wasting and evaluate the prognostic value of each tissue loss. Of all patients treated for aPC from 2013–2019 in Alberta, Canada (n = 504), computed-tomography (CT)-defined muscle and adipose tissue index changes (∆SMI, ∆ATI, cm2/m2) were measured for patients with CT images available both prior to and 12 ± 4 weeks after chemotherapy initiation (n = 210). Contributions of regimen and tumour response to tissue change were assessed with multivariable linear regression. Survival impacts were assessed with multivariable Cox's proportional hazards models. Tissue changes varied widely (∆SMI: −17.8 to +7.3 cm2/m2, ∆ATI: −106.1 to +37.7 cm2/m2) over 116 (27) days. Tumour progression contributed to both muscle and adipose loss (−3.2 cm2/m2, p < 0.001; −12.4 cm2/m2, p = 0.001). FOLFIRINOX was associated with greater muscle loss (−1.6 cm2/m2, p = 0.013) and GEM/NAB with greater adipose loss (−11.2 cm2/m2, p = 0.002). The greatest muscle and adipose losses were independently associated with reduced survival (muscle: HR 1.72, p = 0.007; adipose: HR 1.73, p = 0.012; tertile 1 versus tertile 3). Muscle and adipose losses are adverse effects of chemotherapy and may require regimen-specific management strategies. [ABSTRACT FROM AUTHOR]

Cachexia (CAC) is a debilitating metabolic syndrome. Although dietary interventions are attractive, long-term adherence to specific diets is difficult to maintain and can lead to systemic side effects. Ethyl 3-hydroxybutyrate (EHB) is a commonly used food additive found in wine and Tribolium castaneum. In this study, we investigated the effects of EHB administration in cachectic mice. After a single intraperitoneal injection of EHB into mice, 3-hydroxybutyrate (3-HB) levels were significantly increased in the serum and gastrocnemius of mice. The administration of EHB alleviated cachexia-related symptoms, ameliorated skeletal muscle atrophy, and improved survival in cachectic mice. In addition, the supplementation of cachectic mice with 3-HB by EHB administration significantly reduced tumor weights, indicating the anti-tumor effects of 3-HB. Remarkably, the addition of 3-HB to the culture medium significantly attenuated the C2C12 myotube atrophy induced by the culture supernatant of CT26 cell lines, highlighting its potential to counteract the destructive effects of tumor-derived elements on muscle tissue. NMR-based metabolomics analysis provided insights into the underlying mechanisms and revealed that the anti-cachexia effects of 3-HB treatment can be attributed to three key mechanisms: the promotion of the TCA cycle and the attenuation of proteolysis, the promotion of protein synthesis and the improvement of metabolic homeostasis, and a reduction in inflammation and an enhancement of the antioxidant capacity. This study provided compelling evidence for the protective effects of 3-HB treatment on the cachectic gastrocnemius and highlighted the efficacy of EHB administration as a ketone supplementation approach to achieve nutritional ketosis without the need for dietary restriction. [ABSTRACT FROM AUTHOR]

Quantitative abdominal adipose tissue analysis is important for obtaining information about prognosis and clinical outcomes on a wide array of diseases. In recent years, the effects of abdominal adipose tissue compartments in patients with lymphoma and the changes in their distribution after therapies have been studied. This information could facilitate the improvement of therapies in patients with lymphoma, to prevent or treat both visceral obesity and sarcopenia. Opportunistic analysis of body composition on computed tomography (CT) images might contribute to the improvement of patient management and clinical outcomes together with implementation of targeted patient-tailored therapies. The purpose of this literature review is to describe the role of CT to evaluate abdominal adipose tissue quantity and distribution in patients with lymphoma. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer-related muscle wasting and inflammation, known as cachexia, leads to weight loss and worsened physical function, quality of life (QOL), and survival. The main barrier to current treatments is the lack of improvement in clinically relevant outcomes (function, QOL). Nutraceuticals are naturally occurring food products, which may be of benefit in cancer cachexia. This review describes the effect of nutraceuticals in animal models and in clinical trials in patients with cancer cachexia. Human studies mostly tested fish oil (or something similar) or amino acids (the building blocks of proteins). Body weight was the main focus, while some also assessed muscle mass and QOL, and very few measured physical function. The safety and efficacy of nutraceuticals in treating cancer-related muscle wasting remains uncertain. More animal and large human studies are needed, and they should focus on clinically meaningful outcomes, such as physical function and QOL. Cancer cachexia is largely characterized by muscle wasting and inflammation, leading to weight loss, functional impairment, poor quality of life (QOL), and reduced survival. The main barrier to therapeutic development is a lack of efficacy for improving clinically relevant outcomes, such as physical function or QOL, yet most nutraceutical studies focus on body weight. This review describes clinical and pre-clinical nutraceutical studies outside the context of complex nutritional and/or multimodal interventions, in the setting of cancer cachexia, in view of considerations for future clinical trial design. Clinical studies mostly utilized polyunsaturated fatty acids or amino acids/derivatives, and they primarily focused on body weight and, secondarily, on muscle mass and/or QOL. The few studies that measured physical function almost exclusively utilized handgrip strength with, predominantly, no time and/or group effect. Preclinical studies focused mainly on amino acids/derivatives and polyphenols, assessing body weight, muscle mass, and occasionally physical function. While this review does not provide sufficient evidence of the efficacy of nutraceuticals for cancer cachexia, more preclinical and adequately powered clinical studies are needed, and they should focus on clinically meaningful outcomes, including physical function and QOL. [ABSTRACT FROM AUTHOR]

Simple Summary: Malnutrition, cachexia, and sarcopenia are very common problems in PC patients and are associated with an increased risk of chemotherapy-related toxicity, shorter survival, and reduced quality of life (QoL). Approximately 80% of PC patients report weight loss at diagnosis, and 70.3% of patients develop malnutrition during chemotherapy (CT). Early diagnosis of nutritional problems is the first key point in the proper management of nutritional treatment in patients with pancreatic cancer. Healthcare managers, healthcare professionals, PC patients, and their families should be aware of the importance of nutritional status and the role of nutritional management in clinical outcomes and the quality of life of PC patients. Patients with pancreatic cancer who develop irreversible cancer cachexia have a life expectancy of less than 3 months. Therefore, it is extremely important to evaluate the patient's nutritional status as early as possible and to implement an appropriate nutritional intervention in order to reduce the risk of further weight loss and/or muscle loss, which affect the outcomes of cancer treatment and the correct nutritional treatment in patients with pancreatic cancer. A literature review was performed by using the PubMed and Cochrane quick search methodology. The main purpose of this review was to present the current approach to nutritional treatment in pancreatic cancer. The review included publications, most of which concerned clinical nutrition as part of the phase of treatment of patients with pancreatic cancer, nutritional and metabolic disorders in pancreatic cancer, and the period after pancreatic resection. Some of the publications concerned various nutritional interventions in patients with pancreatic cancer undergoing chemotherapy or surgical treatment (nutritional support before surgery, after surgery, or during palliative treatment). There is an unmet need for integrated nutritional therapy as a key part of the comprehensive care process for PC patients. Nutritional counseling is the first line of nutritional treatment for malnourished cancer patients, but pancreatic enzyme replacement therapy also constitutes the cornerstone of nutritional treatment for relieving symptoms of indigestion and maintaining or improving nutritional status. [ABSTRACT FROM AUTHOR]

Cancer cachexia is a multi-organ syndrome with unintentional weight loss, sarcopenia, and systemic inflammation. Gastrointestinal (GI) cancer patients are more susceptible to cachexia development due to impaired nutrient absorption and digestion. Given the widespread availability and relatively low cost of dietary supplements, we examined the evidence and effects of fish oil (omega-3 fatty acids), melatonin, probiotics, and green tea for managing symptoms of GI cancer cachexia. A literature review of four specific supplements was conducted using PubMed, Google Scholar, and CINAHL without a date restriction. Of 4621 available literature references, 26 articles were eligible for review. Fish oil decreased C-reactive protein and maintained CD4+ cell count, while melatonin indicated inconsistent findings on managing cachexia, but was well-tolerated. Probiotics decreased serum pro-inflammatory biomarkers and increased the tolerability of chemotherapy by reducing side effects. Green tea preparations and extracts showed a decreased risk of developing various cancers and did not impact tumor growth, survival, or adverse effects. Among these four supplements, probiotics are most promising for further research in preventing systemic inflammation and maintaining adequate absorption of nutrients to prevent the progression of cancer cachexia. Supplements may benefit treatment outcomes in cancer cachexia without side effects while supporting nutritional and therapeutic needs. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer cachexia is a multifactorial condition characterized by body weight loss and skeletal muscle wasting that negatively impacts the quality of life and survival of cancer patients. In this paper, we found that ursolic acid (UA) alleviated cancer cachexia and prevented muscle wasting via activating SIRT1, and thence inhibiting phosphorylation levels of NF-κB and STAT3. Furthermore, UA remained effective in the advanced stages of cancer cachexia. This is significant because no approved drug for the treatment of cancer-related muscle atrophy is available. UA may be a potential drug for cancer cachexia and has the possibility of translational application to clinical treatment. Skeletal muscle wasting is the most remarkable phenotypic feature of cancer cachexia that increases the risk of morbidity and mortality. However, there are currently no effective drugs against cancer cachexia. Ursolic acid (UA) is a lipophilic pentacyclic triterpene that has been reported to alleviate muscle atrophy and reduce muscle decomposition in some disease models. This study aimed to explore the role and mechanisms of UA treatment in cancer cachexia. We found that UA attenuated Lewis lung carcinoma (LLC)-conditioned medium-induced C2C12 myotube atrophy and muscle wasting of LLC tumor-bearing mice. Moreover, UA dose-dependently activated SIRT1 and downregulated MuRF1 and Atrogin-1. Molecular docking results revealed a good binding effect on UA and SIRT1 protein. UA rescued vital features wasting without impacting tumor growth, suppressed the elevated spleen weight, and downregulated serum concentrations of inflammatory cytokines in vivo. The above phenomena can be attenuated by Ex-527, an inhibitor of SIRT1. Furthermore, UA remained protective against cancer cachexia in the advanced stage of tumor growth. The results revealed that UA exerts an anti-cachexia effect via activating SIRT1, thereby downregulating the phosphorylation levels of NF-κB and STAT3. UA might be a potential drug against cancer cachexia. [ABSTRACT FROM AUTHOR]

Simple Summary: Approximately half of all patients with advanced cancer experience cachexia, and the prevalence rises above 80% in the last weeks of life. Cancer cachexia (CC) is characterised by anorexia, systemic inflammation, ongoing loss of muscle mass, and weight loss, affecting the quality of life. Different treatments are proposed to manage CC, and comprehensive treatment requires a multidisciplinary approach aimed at evaluating overall patients' conditions and relieving the symptoms, including psycho-social and spiritual functions. Key elements in CC management are personalized, multi-targeted, and multimodal interventions, but it is hard for some patients to follow programs based on several components. We examined the feasibility of a bimodal intervention, including a psycho-educational component and exercises, to support patients and their caregivers in managing CC. Our prospective mixed-methods pilot study explored feasibility data, changes in PROMS and performance outcomes over time, and qualitative data from dyads and healthcare professionals' interviews. Background: Key elements in cancer cachexia (CC) management are personalized and multimodal interventions, but it is hard for some patients to follow programs based on several components. We examined the feasibility of a bimodal intervention, including a psycho-educational component and exercises, to support patients and their caregivers in managing CC; Methods: Prospective mixed-methods pilot study explored feasibility data, changes in patient-reported outcomes, and performance outcomes over time in a convenient sample of 30 consecutive CC patients and their caregivers. Results: Twenty-four dyads consented to participate. Twenty dyads received at least two psycho-educational sessions, so the psycho-educational component was feasible for 83.3% of the sample. Six dyads participated in at least fourteen out of twenty-seven rehabilitation sessions, so the exercise program was feasible for 25.0% of the sample. Six dyads showed compliance greater than 50% for both components of the bimodal intervention. Conclusions: While we did not meet our primary feasibility endpoint and had mixed acceptability, our experience provides insight into the challenges and lessons learned in implementing a primary palliative care intervention for CC. More robust studies are needed to help clinicians understand the best exercise program for CC patients, to be included in a multimodal intervention. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer cachexia is a wasting syndrome mainly driven by chronic inflammation and high energy expenditure. The hyperactivation of the catabolic pathway leads to higher energy utilization by the body. Uncoupling proteins are involved in uncoupling the electron transport chain and thereby halting the ATP production and releasing energy in the form of heat, which increases the body's overall energy utilization. UCPs may play an important role during cancer cachexia. This review aims to highlight the role of UCPs in cancer and cancer cachexia and provide new knowledge to tackle this wasting syndrome. Uncoupling proteins (UCPs) are identified as carriers of proton ions between the mitochondrial inner membrane and the mitochondrial matrix. ATP is mainly generated through oxidative phosphorylation in mitochondria. The proton gradient is generated across the inner mitochondrial membrane and the mitochondrial matrix, which facilitates a smooth transfer of electrons across ETC complexes. Until now, it was thought that the role of UCPs was to break the electron transport chain and thereby inhibit the synthesis of ATP. UCPs allow protons to pass from the inner mitochondrial membrane to the mitochondrial matrix and decrease the proton gradient across the membrane, which results in decreased ATP synthesis and increased production of heat by mitochondria. In recent years, the role of UCPs in other physiological processes has been deciphered. In this review, we first highlighted the different types of UCPs and their precise location across the body. Second, we summarized the role of UCPs in different diseases, mainly metabolic disorders such as obesity and diabetes, cardiovascular complications, cancer, wasting syndrome, neurodegenerative diseases, and kidney complications. Based on our findings, we conclude that UCPs play a major role in maintaining energy homeostasis, mitochondrial functions, ROS production, and apoptosis. Finally, our findings reveal that mitochondrial uncoupling by UCPs may treat many diseases, and extensive clinical studies are required to meet the unmet need of certain diseases. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer cachexia is a metabolic disorder that is associated with poor immunotherapeutic outcomes. However, the circulating cachexia-related cytokines have yet to be longitudinally examined to assess their role in predicting the therapeutic outcomes of PD-1/PD-L1 blockade in advanced lung cancer. This prospective study identified cachexia-related cytokines from a panel of 41 circulating cytokines, which were examined at baseline and during treatment. Our study showed that high IL-6 was associated with a higher risk of immune-related adverse events, while high IL-10 was associated with poor overall survival. More importantly, our study revealed for the first time that an early increase in eotaxin-1 after immunotherapy is a favorable factor related to the therapeutic response to PD-1/PD-L1 blockade and overall survival. These results suggested that the blood-based evaluation of a cachexia-related cytokine network may provide early clues for the immunotherapeutic outcomes. Cancer cachexia is associated with poor immunotherapeutic outcomes. This prospective observational study longitudinally evaluated the role of cachexia-related circulating cytokines in predicting the risk and benefit of PD-1/PD-L1 blockade in advanced lung cancer. Forty-one circulating cytokines at baseline and after one cycle of PD-1/PD-L1 blockade treatment were measured in patients with advanced lung cancer between 2019 and 2020. The cachexia-related cytokines were identified by comparing the levels of circulating cytokines between cachectic and non-cachectic patients. Among 55 patients, 49.1% were diagnosed with cachexia at the beginning of PD-1/PD-L1 blockade therapy. Baseline levels of the circulating cytokines IL-6, IL-8, IL-10, IL-15, and IP-10 were significantly higher in cachectic patients. In contrast, the level of eotaxin-1 was lower in cachectic patients than in those without cachexia. Higher IL-6 at baseline and during treatment was associated with a greater risk of immune-related adverse events, while higher IL-10 at baseline was linked to worse overall survival. More importantly, increased eotaxin-1 after one cycle of PD-1/PD-L1 blockade treatment was associated with higher objective response and better overall survival. A blood-based, cachexia-related cytokine assay may yield potential biomarkers for the early prediction of clinical response to PD-1/PD-L1 blockade and provide clues for improving the outcomes of cachectic patients. [ABSTRACT FROM AUTHOR]

Skeletal muscle is the most abundant tissue in the body and requires high levels of energy to function properly. Skeletal muscle allows voluntary movement and body posture, which require different types of fiber, innervation, energy, and metabolism. Here, we summarize the contribution received at the time of publication of this Introductory Issue for the Special Issue dedicated to "Skeletal Muscle Atrophy: Mechanisms at a Cellular Level". The Special Issue is divided into three sections. The first is dedicated to skeletal muscle pathophysiology, the second to disease mechanisms, and the third to therapeutic development. [ABSTRACT FROM AUTHOR]

Cancer cachexia is a complex multifactorial syndrome whose hallmarks are weight loss due to the wasting of muscle tissue with or without the loss of adipose tissue, anorexia, systemic inflammation, and multi-organ metabolic alterations, which negatively impact patients' response to anticancer treatments, quality of life, and overall survival. Despite its clinical relevance, cancer cachexia often remains an underestimated complication due to the lack of rigorous diagnostic and therapeutic pathways. A number of studies have shown alterations in gut microbiota diversity and composition in association with cancer cachexia markers and symptoms, thus supporting a central role for dysbiosis in the pathogenesis of this syndrome. Different tools of microbiota manipulation, including probiotics, prebiotics, synbiotics, and fecal microbiota transplantation, have been investigated, demonstrating encouraging improvements in cachexia outcomes. Albeit pioneering, these studies pave the way for future research with the aim of exploring the role of gut microbiota in cancer cachexia more deeply and setting up effective microbiota-targeting interventions to be translated into clinical practice. [ABSTRACT FROM AUTHOR]

The present perspective article proposes that cachexia, muscle wasting in cancer, is mediated by dysregulated phosphate metabolism and phosphate toxicity that can damage tissues in most major organ systems. A diet high in phosphorus fed to mice deficient in klotho, a cofactor that regulates phosphate metabolism, accelerates aging, sarcopenia, general organ atrophy, kyphosis, and osteoporosis. Similar effects are seen in phenotypes of mutant p53 mice that overexpress the p53 tumor suppressor gene. Although mutant p53 mice do not develop tumors compared to wild-type mice, mutant p53 mice have shorter mean lifespans. Furthermore, tumorigenesis is associated with the sequestration of excessive inorganic phosphate, and dangerous levels of phosphate are released into circulation during tumor lysis syndrome. In total, this evidence implies that tumorigenesis may be a compensatory mechanism that provides protective effects against systemic exposure to dysregulated phosphate metabolism and phosphate toxicity related to cachexia in cancer. Moreover, the hypothetical protection against phosphate toxicity afforded by tumorigenesis also provides an alternate explanation for putative tumor evasion of the immune system. Insights proposed in this perspective paper provide new directions for further research, with potential to develop novel interventions and clinical applications that modify dietary phosphate intake to reduce cachexia in cancer patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer cachexia is an underestimated condition with huge impact on survival and quality of life for many cancer patients. Currently, there is no reliable diagnosis for this condition, particularly for cancer cachexia at an early stage. The aim of our study is to develop potential biomarkers that can be used not only for diagnosing cancer cachexia but also evaluating potential anti-cachexia therapy such as anti-Fn14 mAb treatment. We identified several circulating biomarkers for cancer cachexia and confirmed that LCN2 is a promising biomarker for cancer cachexia in humans. These biomarkers could accelerate both diagnosis and clinical trials for cancer cachexia. Background: Developing therapies for cancer cachexia has not been successful to date, in part due to the challenges of achieving robust quantitative measures as a readout of patient treatment. Hence, identifying biomarkers to assess the outcomes of treatments for cancer cachexia is of great interest and important for accelerating future clinical trials. Methods: We established a novel xenograft model for cancer cachexia with a cachectic human PC3* cell line, which was responsive to anti-Fn14 mAb treatment. Using RNA-seq and secretomic analysis, genes differentially expressed in cachectic and non-cachectic tumors were identified and validated by digital droplet PCR (ddPCR). Correlation analysis was performed to investigate their impact on survival in cancer patients. Results: A total of 46 genes were highly expressed in cachectic PC3* tumors, which were downregulated by anti-Fn14 mAb treatment. High expression of the top 10 candidates was correlated with low survival and high cachexia risk in different cancer types. Elevated levels of LCN2 were observed in serum samples from cachectic patients compared with non-cachectic cancer patients. Conclusion: The top 10 candidates identified in this study are candidates as potential biomarkers for cancer cachexia. The diagnostic value of LCN2 in detecting cancer cachexia is confirmed in patient samples. [ABSTRACT FROM AUTHOR]

Simple Summary: Immunotherapy has revolutionized the therapeutic options for patients living with non-small-cell lung cancer (NSCLC). Despite the unprecedented results achieved through immunotherapy, a low body mass index, which is referred to as cachexia, and the bacterial composition of the gut microbiota are known factors associated with resistance. In this paper, we enrolled 113 Japanese patients with NSCLC and demonstrated that cachexia was associated with poor outcomes. Moreover, microbiota sequencing revealed that patients without cachexia had abundant bacteria that correlated with a beneficial outcome. Altogether, our results demonstrated an association between the gut microbiota and cachexia. This study provides a rationale to launch clinical trials on the outcome of shifting the microbiota composition of patients with cachexia that are receiving immunotherapy. Cancer cachexia exerts a negative clinical influence on patients with advanced non-small-cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICI). The prognostic impact of body weight change during ICI treatment remains unknown. The gut microbiota (GM) is a key contributor to the response to ICI therapy in cancer patients. However, the association between cancer cachexia and GM and their association with the response to ICIs remains unexplored. This study examined the association of cancer cachexia with GM composition and assessed the impact of GM on clinical outcomes in patients with NSCLC treated with ICIs. In this observational, prospective study, which included 113 Japanese patients with advanced NSCLC treated with ICIs, the prevalence of cachexia was 50.4% (57/113). The median progression-free survival (PFS) and overall survival (OS) were significantly shorter in the cachexia group than in the non-cachexia group (4.3 vs. 11.6 months (p = 0.003) and 12.0 months vs. not reached (p = 0.02), respectively). A multivariable analysis revealed that baseline cachexia was independently associated with a shorter PFS. Moreover, a gain in body weight from the baseline (reversible cachexia) was associated with a significantly longer PFS and OS compared to irreversible cachexia. Microbiome profiling with 16S rRNA analysis revealed that the cachexia group presented an overrepresentation of the commensal bacteria, Escherichia-Shigella and Hungatella, while the non-cachexia group had a preponderance of Anaerostipes, Blautia, and Eubacterium ventriosum. Anaerostipes and E. ventriosum were associated with longer PFS and OS. Moreover, a cachexia status correlated with the systemic inflammatory marker-derived-neutrophil-to-lymphocytes ratio (dNLR) and Lung Immune Prognostic Index (LIPI) indexes. Our study demonstrates that cachexia and longitudinal bodyweight change have a prognostic impact on patients with advanced NSCLC treated with ICI therapy. Moreover, our study demonstrates that bacteria associated with ICI resistance are also linked to cachexia. Targeted microbiota interventions may represent a new type of treatment to overcome cachexia in patients with NSCLC. [ABSTRACT FROM AUTHOR]

Simple Summary: Data on the efficacy and safety of pharmacotherapy for advanced non-small cell lung cancer (NSCLC) with poor performance status (PS) 2 are insufficient. Cytotoxic chemotherapy for patients with PS 2 is insufficiently effective, and there are concerns about toxicity. Immune checkpoint inhibitors are a promising treatment with the potential for less severe toxicity, but data are more limited than with cytotoxic chemotherapy. In this review article, we summarize the current evidence on pharmacotherapy for NSCLC patients with PS 2 and without druggable genetic alterations, and we discuss future perspectives and challenges. Most pivotal clinical trials in advanced non-small cell lung cancer (NSCLC) have excluded patients with poor performance status (PS), and data on the efficacy and safety of pharmacotherapy have not been fully accumulated. For NSCLC patients with PS 2 and without druggable genetic alterations, monotherapy with cytotoxic agents or carboplatin-based combination therapy is usually administered based on the results of several randomized trials. However, the evidence of cytotoxic chemotherapy for patients with PS 2 is insufficient, with limited efficacy and toxicity concerns. Immune checkpoint inhibitors (ICIs) are a promising treatment for patients with PS 2 because of lower incidence of severe toxicity compared to cytotoxic chemotherapy. Meanwhile, several reports suggest that anti-PD-1 antibodies monotherapy is less effective for patients with PS 2, especially for those with PS 2 caused by disease burden. Although the combination therapy of nivolumab and ipilimumab is a promising treatment option, there is a divergence in efficacy data between clinical trials. The standard of care for advanced NSCLC with PS 2 has not been established, and future therapeutic strategies should take into account the heterogeneity of the PS 2 population. [ABSTRACT FROM AUTHOR]

Cachexia is characterized by progressive weight loss accompanied by the loss of specific skeletal muscle and adipose tissue. Increased lactate production, either due to the Warburg effect from tumors or accelerated glycolysis effects from cachectic muscle, is the most dangerous factor for cancer cachexia. This study aimed to explore the efficiency of 2-deoxy-D-glucose (2-DG) in blocking Cori cycle activity and its therapeutic effect on cachexia-associated muscle wasting. A C26 adenocarcinoma xenograft model was used to study cancer cachectic metabolic derangements. Tumor-free lean mass, hindlimb muscle morphology, and fiber-type composition were measured after in vivo 2-DG administration. Activation of the ubiquitin-dependent proteasome pathway (UPS) and autophagic–lysosomal pathway (ALP) was further assessed. The cachectic skeletal muscles of tumor-bearing mice exhibited altered glucose and lipid metabolism, decreased carbohydrate utilization, and increased lipid β-oxidation. Significantly increased gluconeogenesis and decreased ketogenesis were observed in cachectic mouse livers. 2-DG significantly ameliorated cancer cachexia-associated muscle wasting and decreased cachectic-associated lean mass levels and fiber cross-sectional areas. 2-DG inhibited protein degradation-associated UPS and ALP, increased ketogenesis in the liver, and promoted ketone metabolism in skeletal muscle, thus enhancing mitochondrial bioenergetic capacity. 2-DG effectively prevents muscle wasting by increasing ATP synthesis efficiency via the ketone metabolic pathway and blocking the abnormal Cori cycle. [ABSTRACT FROM AUTHOR]

Skeletal muscle homeostasis is essential for the maintenance of a healthy and active lifestyle. Imbalance in muscle homeostasis has significant consequences such as atrophy, loss of muscle mass, and progressive loss of functions. Aging-related muscle wasting, sarcopenia, and atrophy as a consequence of disease, such as cachexia, reduce the quality of life, increase morbidity and result in an overall poor prognosis. Investigating the muscle proteome related to muscle atrophy diseases has a great potential for diagnostic medicine to identify (i) potential protein biomarkers, and (ii) biological processes and functions common or unique to muscle wasting, cachexia, sarcopenia, and aging alone. We conducted a meta-analysis using gene ontology (GO) analysis of 24 human proteomic studies using tissue samples (skeletal muscle and adipose biopsies) and/or biofluids (serum, plasma, urine). Whilst there were few similarities in protein directionality across studies, biological processes common to conditions were identified. Here we demonstrate that the GO analysis of published human proteomics data can identify processes not revealed by single studies. We recommend the integration of proteomics data from tissue samples and biofluids to yield a comprehensive overview of the human skeletal muscle proteome. This will facilitate the identification of biomarkers and potential pathways of muscle-wasting conditions for use in clinics. [ABSTRACT FROM AUTHOR]

According to the World Health Organization, in 2018, cancers, along with over 18 million new cases and over 9.5 million deaths remained one of the main causes of mortality globally. Cancer-cachexia, also called wasting syndrome is a complex, multifactorial disorder characterized by progressive skeletal muscle mass loss, with or without adipose tissue atrophy. It is considered as a state of cancer-related malnutrition (CRM) accompanied by inflammation, that is irreversible despite the introduction of nutritional support. Indication of markers of pre-cachectic state seems to be urgently needed. Moreover, such markers have also potential to be used in the assessment of the effects of anti-cachexia treatment, and prognosis. miRNAs are non-coding RNA molecules that are about 20–30 nucleotides long. Single miRNA has the potential to control from few dozen to several hundred different genes. Despite the fact, that the number of miRNAs keep growing. we are making steady progress in establishing regulatory targets and their physiological levels. In this review we described the current knowledge on the impact of miRNAs on processes involved in cancer cachexia development: inflammation, adipose tissue remodelling, and loss of muscle mass both in animal models and the human cohorts. The available studies suggest that miRNAs, due to their properties, e.g., the possibility of regulating even hundreds of different genes, signalling pathways, and biological processes by one molecule, but also due their stability in biological material, the fact, that the change in their level reflects the disease status or the response to the applied treatment, they have great potential to be used as valuable biomarkers in the diagnosis, treatment, and prognosis of cancer cachexia. [ABSTRACT FROM AUTHOR]

Carotenoids are organic, liposoluble pigments found in nature, which are responsible for the characteristic colors of ripe tomatoes, carrots, peppers, and crustaceans, among others. Palliative care provided to patients with an incurable disease is aimed at improving the patient's quality of life through appropriate treatment of symptoms accompanying the disease. Palliative care patients with burdensome symptoms related to advanced-stage cancers are especially interested in the use of natural dietary supplements and herbal remedies to reduce symptoms' intensity and ameliorate the quality of life. Carotenoids seem to be a group of natural compounds with particularly promising properties in relieving symptoms, mainly due to their strong antioxidant, anti-inflammatory, and neuroprotective properties. Moreover, carotenoids have been used in folk medicine to treat various diseases and alleviate the accompanying symptoms. In this narrative review, the authors decided to determine whether there is any scientific evidence supporting the rationale for carotenoid supplementation in advanced-stage cancer patients, with particular emphasis on the adjuvant treatment of cancer-related symptoms, such as neuropathic pain and cancer-related cachexia. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic cancer (PC) is one of the most lethal malignancies across the world. More than 80% patients are diagnosed at an advanced stage with limited treatment options. PC has the highest frequency of developing cancer cachexia (CC)–sarcopenia (SC) syndrome, but there is no optimal efficient intervention for CC or SC targeting their complicated biological and irreversible processes. As a result, identifying the clinicopathological features and patient characteristics in each advanced PC patient with CC and/or SC is urgently needed to distinguish different wasting phenotypes or body composition and thus support precision medicine and achieve optimal outcomes. We performed a retrospective cohort study of 232 advanced PC patients to determine the differential clinical characteristics of CC and SC and the overlap of CC- or SC-related factors in each patient. The impacts of CC, SC, and their relevant factors on the outcomes of PC patients were also evaluated. Pancreatic cancer (PC) has the highest frequency of developing cancer cachexia (CC)–sarcopenia (SC) syndrome, which negatively influences patients' outcome, quality of life, and tolerance/response to treatments. However, the clinical impacts of CC, SC, and their associated factors on outcomes for advanced PC has yet to be fully investigated. A total of 232 patients were enrolled in this study for the retrospective review of their clinical information and the measurement of skeletal muscle areas at the third lumber vertebra by computed tomography scan to identify CC or SC. The association and concurrent occurrence of clinicopathological features in each patient, prevalence rates, and prognosis with the CC or SC were calculated. CC and SC were observed in 83.6% (n = 194) and 49.1% (n = 114) of PC patients, respectively. Low hemoglobin levels more often occurred in CC patients than in non-CC patients (p = 0.014). Older age (p = 0.000), female gender (p = 0.024), low body mass index (BMI) values (p = 0.004), low hemoglobin levels (p = 0.036), and low albumin levels (p = 0.001) were more often found in SC patients than in non-SC patients. Univariate and multivariate analyses showed that CC was an independent poor prognostic factor of overall survival (OS) and progression-free survival for all patients, the chemotherapy (C/T) subgroup, and the high BMI subgroup. Meanwhile, SC was an independent predictor of poor OS for the subgroups of C/T or high BMI but not for all patients. These findings reveal the clinical differences for CC and SC and provide useful information for predicting the prognosis of advanced PC patients and conducting personalized medicine. [ABSTRACT FROM AUTHOR]

Cancer cachexia is a syndrome of progressive weight loss and muscle wasting occurring in many advanced cancer patients. Cachexia significantly impairs quality of life and increases mortality. Cardiac atrophy and dysfunction have been observed in patients with cachexia, which may contribute to cachexia pathophysiology. However, relative to skeletal muscle, little research has been carried out to understand the mechanisms of cardiomyopathy in cachexia. Here, we review what is known clinically about the cardiac changes occurring in cachexia, followed by further discussion of underlying physiological and molecular mechanisms contributing to cachexia-induced cardiomyopathy. Impaired cardiac contractility and relaxation may be explained by a complex interplay of significant heart muscle atrophy and metabolic remodeling, including mitochondrial dysfunction. Because cardiac muscle has fundamental differences compared to skeletal muscle, understanding cardiac-specific effects of cachexia may bring light to unique therapeutic targets and ultimately improve clinical management for patients with cancer cachexia. [ABSTRACT FROM AUTHOR]

The crosstalk between tumors and their local microenvironment has been well studied, whereas the effect of tumors on distant tissues remains understudied. Studying how tumors affect other tissues is important for understanding the systemic effect of tumors and for improving the overall health of cancer patients. In this study, we focused on the changes in the intestine during liver tumor progression, using a previously established liver tumor model through inducible expression of the oncogene xmrk in zebrafish. Progressive disruption of intestinal structure was found in the tumor fish, displaying villus damage, thinning of bowel wall, increase in goblet cell number, decrease in goblet cell size and infiltration of eosinophils, most of which were observed phenotypes of an inflammatory intestine. Intestinal epithelial cell renewal was also disrupted, with decreased cell proliferation and increased cell death. Analysis of intestinal gene expression through RNA-seq suggested deregulation of genes related to intestinal function, epithelial barrier and homeostasis and activation of pathways in inflammation, epithelial mesenchymal transition, extracellular matrix organization, as well as hemostasis. Gene set enrichment analysis showed common gene signatures between the intestine of liver tumor fish and human inflammatory bowel disease, the association of which with cancer has been recently noticed. Overall, this study represented the first systematic characterization of the disruption of intestine under the liver tumor condition and suggested targeting intestinal inflammation as a potential approach for managing cancer cachexia. [ABSTRACT FROM AUTHOR]

Cancer cachexia syndrome (CCS) is a multifactorial metabolic syndrome affecting a significant proportion of patients. CCS is characterized by progressive weight loss, alterations of body composition and a systemic inflammatory status, which exerts a major impact on the host's innate and adaptive immunity. Over the last few years, the development of immune checkpoint inhibitors (ICIs) transformed the treatment landscape for a wide spectrum of malignancies, creating an unprecedented opportunity for long term remissions in a significant subset of patients. Early clinical data indicate that CCS adversely impairs treatment outcomes of patients receiving ICIs. We herein reviewed existing evidence on the potential links between the mechanisms that promote the catabolic state in CCS and those that impair the antitumor immune response. We show that the biological mediators and processes leading to the development of CCS may also participate in the modulation and the sustainment of an immune suppressive tumor microenvironment and impaired anti-tumor immunity. Moreover, we demonstrate that the deregulation of the host's metabolic homeostasis in cancer cachexia is associated with resistance to ICIs. Further research on the interrelation between cancer cachexia and anti-tumor immunity is required for the effective management of resistance to immunotherapy in this specific but large subgroup of ICI treated individuals. [ABSTRACT FROM AUTHOR]

Skeletal muscle wasting critically impairs the survival and quality of life in patients with pancreatic ductal adenocarcinoma (PDAC). To identify the local factors initiating muscle wasting, we studied inflammation, fiber cross-sectional area (CSA), composition, amino acid metabolism and capillarization, as well as the integrity of neuromuscular junctions (NMJ, pre-/postsynaptic co-staining) and mitochondria (electron microscopy) in the hindlimb muscle of LSL-KrasG12D/+; LSL-TrP53R172H/+; Pdx1-Cre mice with intraepithelial-neoplasia (PanIN) 1-3 and PDAC, compared to wild-type mice (WT). Significant decreases in fiber CSA occurred with PDAC but not with PanIN 1-3, compared to WT: These were found in the gastrocnemius (type 2x: −20.0%) and soleus (type 2a: −21.0%, type 1: −14.2%) muscle with accentuation in the male soleus (type 2a: −24.8%, type 1: −17.4%) and female gastrocnemius muscle (−29.6%). Significantly higher densities of endomysial CD68+ and cyclooxygenase-2+ (COX2+) cells were detected in mice with PDAC, compared to WT mice. Surprisingly, CD68+ and COX2+ cell densities were also higher in mice with PanIN 1-3 in both muscles. Significant positive correlations existed between muscular and hepatic CD68+ or COX2+ cell densities. Moreover, in the gastrocnemius muscle, suppressor-of-cytokine-3 (SOCS3) expressions was upregulated >2.7-fold with PanIN 1A-3 and PDAC. The intracellular pools of proteinogenic amino acids and glutathione significantly increased with PanIN 1A-3 compared to WT. Capillarization, NMJ, and mitochondrial ultrastructure remained unchanged with PanIN or PDAC. In conclusion, the onset of fiber atrophy coincides with the manifestation of PDAC and high-grade local (and hepatic) inflammatory infiltration without compromised microcirculation, innervation or mitochondria. Surprisingly, muscular and hepatic inflammation, SOCS3 upregulation and (proteolytic) increases in free amino acids and glutathione were already detectable in mice with precancerous PanINs. Studies of initial local triggers and defense mechanisms regarding cachexia are warranted for targeted anti-inflammatory prevention. [ABSTRACT FROM AUTHOR]

Simple Summary: The primary characteristics of cancer cachexia are weakness, weight loss, atrophy, fat reduction, and systemic inflammation. Cachexia is strongly associated with cancers involving the lungs, pancreas, esophagus, stomach, and liver, which account for half of all cancer deaths. TGF-β, MSTN, activin, IGF-1/PI3K/AKT, and JAK-STAT signaling pathways are known to underlie muscle atrophy and cachexia. Anamorelin (appetite stimulation), megestrol acetate, eicosapentaenoic acid, phytocannabinoids, targeting MSTN/activin, and molecules targeting proinflammatory cytokines, such as TNF-α and IL-6, are being tested as treatment options for cancer cachexia. Cancer cachexia is a condition marked by functional, metabolic, and immunological dysfunctions associated with skeletal muscle (SM) atrophy, adipose tissue loss, fat reduction, systemic inflammation, and anorexia. Generally, the condition is caused by a variety of mediators produced by cancer cells and cells in tumor microenvironments. Myostatin and activin signaling, IGF-1/PI3K/AKT signaling, and JAK-STAT signaling are known to play roles in cachexia, and thus, these pathways are considered potential therapeutic targets. This review discusses the current state of knowledge of the molecular mechanisms underlying cachexia and the available therapeutic options and was undertaken to increase understanding of the various factors/pathways/mediators involved and to identify potential treatment options. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer cachexia is a highly debilitating syndrome involving severe body weight loss. Worldwide around 9–14.5 million cancer patients suffer from cachexia every year and many of them die because of cachexia. Our study aimed to assess the possible role of apelin against muscle loss during cancer growth given its beneficial effects against muscle atrophy during aging. We found apelin exhibiting advantageous effects against atrophy in in vitro models, but not in in vivo models, where we unraveled undesirable apelin resistance that may nullify apelin-based therapy for cancer cachexia. Cancer cachexia consists of dramatic body weight loss with rapid muscle depletion due to imbalanced protein homeostasis. We found that the mRNA levels of apelin decrease in muscles from cachectic hepatoma-bearing rats and three mouse models of cachexia. Furthermore, apelin expression inversely correlates with MuRF1 in muscle biopsies from cancer patients. To shed light on the possible role of apelin in cachexia in vivo, we generated apelin 13 carrying all the last 13 amino acids of apelin in D isomers, ultimately extending plasma stability. Notably, apelin D-peptides alter cAMP-based signaling in vitro as the L-peptides, supporting receptor binding. In vitro apelin 13 protects myotube diameter from dexamethasone-induced atrophy, restrains rates of degradation of long-lived proteins and MuRF1 expression, but fails to protect mice from atrophy. D-apelin 13 given intraperitoneally for 13 days in colon adenocarcinoma C26-bearing mice does not reduce catabolic pathways in muscles, as it does in vitro. Puzzlingly, the levels of circulating apelin seemingly deriving from cachexia-inducing tumors, increase in murine plasma during cachexia. Muscle electroporation of a plasmid expressing its receptor APJ, unlike apelin, preserves myofiber area from C26-induced atrophy, supporting apelin resistance in vivo. Altogether, we believe that during cachexia apelin resistance occurs, contributing to muscle wasting and nullifying any possible peptide-based treatment. [ABSTRACT FROM AUTHOR]

Cancer cachexia is a debilitating syndrome characterized by progressive weight loss, muscle wasting, and systemic inflammation. Despite the prevalence and severe consequences of cancer cachexia, effective treatments for this syndrome remain elusive. Therefore, there is a greater need for well-characterized animal models to identify novel therapeutic targets. Certain manifestations of cachexia, such as pain and depression, have been extensively studied using animal models of cancer-induced bone pain (CIBP). In contrast, other aspects of cachexia have received less attention in these models. To address this issue, we established the CIBP model by injecting Lewis lung carcinoma into the intramedullary cavity of the femur, observed cachexia-related symptoms, and demonstrated the utility of this model as a preclinical platform to study cancer cachexia. This model accurately recapitulates key features of cancer cachexia, including weight loss, muscle atrophy, adipose tissue depletion, CIBP, and anxiety. These findings suggest that psychological factors, in addition to physiological and metabolic factors, play significant roles in cancer cachexia development. Our model offers a valuable resource for investigating the underlying mechanisms of cancer cachexia and for developing innovative therapeutic strategies that target physical and psychological components.

The ketogenic diet (KD) is characterized by minimal carbohydrate, moderate protein, and high fat intake, leading to ketosis. It is recognized for its efficiency in weight loss, metabolic health improvement, and various therapeutic interventions. The KD enhances glucose and lipid metabolism, reducing triglycerides and total cholesterol while increasing high-density lipoprotein levels and alleviating dyslipidemia. It significantly influences adipose tissue hormones, key contributors to systemic metabolism. Brown adipose tissue, essential for thermogenesis and lipid combustion, encounters modified UCP1 levels due to dietary factors, including the KD. UCP1 generates heat by uncoupling electron transport during ATP synthesis. Browning of the white adipose tissue elevates UCP1 levels in both white and brown adipose tissues, a phenomenon encouraged by the KD. Ketone oxidation depletes intermediates in the Krebs cycle, requiring anaplerotic substances, including glucose, glycogen, or amino acids, for metabolic efficiency. Methylation is essential in adipogenesis and the body's dietary responses, with DNA methylation of several genes linked to weight loss and ketosis. The KD stimulates FGF21, influencing metabolic stability via the UCP1 pathways. The KD induces a reduction in muscle mass, potentially involving anti-lipolytic effects and attenuating proteolysis in skeletal muscles. Additionally, the KD contributes to neuroprotection, possesses anti-inflammatory properties, and alters epigenetics. This review encapsulates the metabolic effects and signaling induced by the KD in adipose tissue and major metabolic organs.

Low-carbohydrate, high-fat diets (ketogenic diets) might prevent tumor progression and could be used as supportive therapy; however, few studies have addressed the effect of such diets on colorectal cancer. An infant formula with a ketogenic composition (ketogenic formula; KF) is used to treat patients with refractory epilepsy. We investigated the effect of KF on cancer and cancer cachexia in colon tumor-bearing mice. Mice were randomized into normal (NR), tumor-bearing (TB), and ketogenic formula (KF) groups. Colon 26 cells were inoculated subcutaneously into TB and KF mice. The NR and TB groups received a standard diet, and the KF mice received KF ad libitum. KF mice preserved their body, muscle, and carcass weights. Tumor weight and plasma IL-6 levels were significantly lower in KF mice than in TB mice. In the KF group, energy intake was significantly higher than that in the other two groups. Blood ketone body concentrations in KF mice were significantly elevated, and there was a significant negative correlation between blood ketone body concentration and tumor weight. Therefore, KF may suppress the progression of cancer and the accompanying systemic inflammation without adverse effects on weight gain, or muscle mass, which might help to prevent cancer cachexia. [ABSTRACT FROM AUTHOR]