Cancer cachexia is an involuntary loss of body weight, mostly of skeletal muscle. Previous research favors the existence of a microbiota-muscle crosstalk, so the aim of the study was to evaluate the impact of microbiota alterations induced by antibiotics on skeletal muscle proteins expression. Skeletal muscle proteome changes were investigated in control (CT) or C26 cachectic mice (C26) with or without antibiotic treatment (CT-ATB or C26-ATB, n = 8 per group). Muscle protein extracts were divided into a sarcoplasmic and myofibrillar fraction and then underwent label-free liquid chromatography separation, mass spectrometry analysis, Mascot protein identification, and METASCAPE platform data analysis. In C26 mice, the atrogen mafbx expression was 353% higher than CT mice and 42.3% higher than C26-ATB mice. No effect on the muscle protein synthesis was observed. Proteomic analyses revealed a strong effect of antibiotics on skeletal muscle proteome outside of cachexia, with adaptative processes involved in protein folding, growth, energy metabolism, and muscle contraction. In C26-ATB mice, proteome adaptations observed in CT-ATB mice were blunted. Differentially expressed proteins were involved in other processes like glucose metabolism, oxidative stress response, and proteolysis. This study confirms the existence of a microbiota-muscle axis, with a muscle response after antibiotics that varies depending on whether cachexia is present.

The commonality between various muscle diseases is the loss of muscle mass, function, and regeneration, which severely restricts mobility and impairs the quality of life. With muscle stem cells (MuSCs) playing a key role in facilitating muscle repair, targeting regulators of muscle regeneration has been shown to be a promising therapeutic approach to repair muscles. However, the underlying molecular mechanisms driving muscle regeneration are complex and poorly understood. Here, we identified a new regulator of muscle regeneration, Deaf1 (Deformed epidermal autoregulatory factor-1) - a transcriptional factor downstream of foxo signaling. We showed that Deaf1 is transcriptionally repressed by FOXOs and that DEAF1 targets to Pik3c3 and Atg16l1 promoter regions and suppresses their expression. Deaf1 depletion therefore induces macroautophagy/autophagy, which in turn blocks MuSC survival and differentiation. In contrast, Deaf1 overexpression inactivates autophagy in MuSCs, leading to increased protein aggregation and cell death. The fact that Deaf1 depletion and its overexpression both lead to defects in muscle regeneration highlights the importance of fine tuning DEAF1-regulated autophagy during muscle regeneration. We further showed that Deaf1 expression is altered in aging and cachectic MuSCs. Manipulation of Deaf1 expression can attenuate muscle atrophy and restore muscle regeneration in aged mice or mice with cachectic cancers. Together, our findings unveil an evolutionarily conserved role for DEAF1 in muscle regeneration, providing insights into the development of new therapeutic strategies against muscle atrophy.

UNASSIGNED: Cancer cachexia is associated with poor prognosis in patients with metastatic urothelial carcinoma (mUC). The objective of the study was to assess the cachexia index (CXI), which is a new indicator assessing the status of cancer cachexia, as a prognostic indicator for mUC patients treated with gemcitabine plus cisplatin (GC) chemotherapy.
UNASSIGNED: The study included 55 patients with mUC who underwent GC chemotherapy between 2008 and 2022 as first-line chemotherapy. The CXI at the start of chemotherapy was determined as follows: CXI=(serum albumin × skeletal muscle mass index)/ (neutrophil count/lymphocyte count). Patients were categorized into two groups based on a median CXI value (CXI-high and CXI low). We used Kaplan-Meier curves and multivariate Cox proportional hazards regression models to assess the association between the CXI and overall survival (OS).
UNASSIGNED: At the start of GC chemotherapy, significant differences were not found in patients\' characteristics. The median OS was significantly shorter in the CXI-low group [10.0 months (95% confidence interval (CI)=5.1-12.8)] than in the CXI-high group [22.3 months (95% CI=13.6-NA), p<0.05]. Multivariate analysis revealed that low CXI was a predictor of a poor prognosis [hazard ratio (HR)=2.25, 95% CI=1.12-4.52, p<0.05].
UNASSIGNED: CXI might be useful as a prognostic indicator for patients with mUC undergoing first-line GC chemotherapy.

Cancer cachexia is a multifactorial syndrome associated with advanced cancer that contributes to mortality. Cachexia is characterized by loss of body weight and muscle atrophy. Increased skeletal muscle mitochondrial reactive oxygen species (ROS) is a contributing factor to loss of muscle mass in cachectic patients. Mice inoculated with Lewis lung carcinoma (LLC) cells lose weight, muscle mass, and have lower muscle sirtuin-1 (sirt1) expression. Nicotinic acid (NA) is a precursor to nicotinamide dinucleotide (NAD+) which is exhausted in cachectic muscle and is a direct activator of sirt1. Mice lost body and muscle weight and exhibited reduced skeletal muscle sirt1 expression after inoculation with LLC cells. C2C12 myotubes treated with LLC-conditioned media (LCM) had lower myotube diameter. We treated C2C12 myotubes with LCM for 24 h with or without NA for 24 h. C2C12 myotubes treated with NA maintained myotube diameter, sirt1 expression, and had lower mitochondrial superoxide. We then used a sirt1-specific small molecule activator SRT1720 to increase sirt1 activity. C2C12 myotubes treated with SRT1720 maintained myotube diameter, prevented loss of sirt1 expression, and attenuated mitochondrial superoxide production. Our data provides evidence that NA may be beneficial in combating cancer cachexia by maintaining sirt1 expression and decreasing mitochondrial superoxide production.

BACKGROUND: The modified Glasgow Prognostic Score (mGPS) and Prognostic Nutritional Index (PNI) are indicators of nutritional status in cancer patients; however, the effects of baseline mGPS and PNI on the duration of administration of the ghrelin receptor agonist anamorelin, which is used to treat cachexia in patients with cancer, are unclear. This study aimed to clarify the association of mGPS and PNI with the duration of oral anamorelin administration for patients who did not have beneficial effects from anamorelin.
METHODS: The attending physician determined the duration of oral anamorelin administration based on discontinuation due to cancer progression, poor efficacy, adverse events, or death.
RESULTS: The 12-week continuation rate of oral anamorelin was 30.4%. Univariate analysis revealed that an Eastern Cooperative Oncology Group performance status (ECOG-PS) of ≥2 (P < .001), concurrent chemotherapy (P = .002), albumin level (P = .005), C-reactive protein level (P = .013), and a mGPS of 2 (P = .014) were statistically significant predictors of the 12-week continuation rate of oral anamorelin. In the multivariate analysis, a mGPS of 2 remained a significant risk factor, and the ECOG-PS and concurrent chemotherapy had no effect on the association between the mGPS and 12-week continuation rate of oral anamorelin.
CONCLUSIONS: Patients with a mGPS of 2, compared with mGPS of 0 or 1, are less likely to maintain oral anamorelin therapy, regardless of the ECOG-PS or concurrent chemotherapy. Therefore, it is necessary to consider initiating anamorelin administration at mGPS 0 or 1.

SUMMARYThe gut microbiota is a major factor contributing to the regulation of energy homeostasis and has been linked to both excessive body weight and accumulation of fat mass (i.e., overweight, obesity) or body weight loss, weakness, muscle atrophy, and fat depletion (i.e., cachexia). These syndromes are characterized by multiple metabolic dysfunctions including abnormal regulation of food reward and intake, energy storage, and low-grade inflammation. Given the increasing worldwide prevalence of obesity, cachexia, and associated metabolic disorders, novel therapeutic strategies are needed. Among the different mechanisms explaining how the gut microbiota is capable of influencing host metabolism and energy balance, numerous studies have investigated the complex interactions existing between nutrition, gut microbes, and their metabolites. In this review, we discuss how gut microbes and different microbiota-derived metabolites regulate host metabolism. We describe the role of the gut barrier function in the onset of inflammation in this context. We explore the importance of the gut-to-brain axis in the regulation of energy homeostasis and glucose metabolism but also the key role played by the liver. Finally, we present specific key examples of how using targeted approaches such as prebiotics and probiotics might affect specific metabolites, their signaling pathways, and their interactions with the host and reflect on the challenges to move from bench to bedside.

OBJECTIVE: The characterization and prognostic value of body composition parameter/phenotype based on computed tomography (CT) in patients with digestive tract cancers remain incomplete. This study aimed to investigate the relationship between parameter/phenotype and clinical outcomes in patients with digestive tract cancers.
METHODS: In this prospective cohort study, 8267 patients with digestive tract cancers were assessed using CT scans to determine body composition. Body composition data, including areas of skeletal muscle (SM), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT), were collected at the third lumbar level on CT images obtained within 30 days before surgery. Body composition phenotypes (sarcopenia, cancer cachexia, sarcopenic obesity) were determined based on SM, SAT, and VAT areas. The primary endpoint was overall survival, obtained from electronic medical records and telephone follow-up surveys. Kaplan-Meier and log-rank analyses were employed to compare unadjusted survival, while multivariate survival analyses were conducted using a proportional hazards model adjusted for age, gender, and cancer-node-metastasis (TNM) stages.
RESULTS: Adjusted hazard ratios (HRs) for all-cause mortality were calculated for the second (Q2), third (Q3), and fourth (Q4) quantiles relative to the first quantile (Q1) for SM areas, revealing adjusted summary HRs of 0.575 (95% CI, 0.361-0.916), 0.419 (95% CI, 0.241-0.729), and 0.384 (95% CI, 0.203-0.726), respectively. Sarcopenia-adjusted summary HRs were 1.795 (95% CI: 1.012-3.181) for male patients and 1.925 (95% CI: 1.065-3.478) for female patients. Cancer cachexia-adjusted summary HRs were 1.542 (95% CI: 1.023-2.324) for male patients and 1.569 (95% CI: 0.820-3.001) for female patients. Sarcopenic obesity-adjusted summary HRs were 1.122 (95% CI: 0.759-1.657) for male patients and 1.303 (95% CI: 0.623-2.725) for female patients. Subgroup analyses indicated varying prognostic values of body composition parameter/phenotype among different cancer types.
CONCLUSIONS: Our findings suggest a large SM area is a favorable prognostic indicator, while cancer cachexia and sarcopenia signify poor prognosis in patients with digestive tract cancers. These findings have important implications for the personalized preoperative assessment of body composition in patients with digestive tract cancers.

OBJECTIVE: Patients with advanced pancreatic and biliary tract cancer (aPBC) frequently suffer from high symptom burden. Exercise can reduce treatment side effects and improve patient-related outcomes (PROMs). However, evidence from prospective studies regarding feasibility and efficacy in advanced settings are sparse. The primary aim of this prospective, randomized-controlled study was to evaluate the feasibility and effects of exercise (ET) in patients with aPBC.
METHODS: Patients with aPBC beyond first-line therapy were randomized according to the minimization procedure with stratification by gender, age, and loss of body weight in the past six months. The intervention group (IG) completed 3 training units/week for 8 weeks (1x supervised strength sessions, 2x individualized home-based sessions). Control group (CG) received recommendations on physical activity during cancer.
RESULTS: 41 patients (stage IV pancreatic or biliary tract cancer) were included no adverse events related to exercise occurred during the trial. Physical function increased significantly in IG in 5 out of 7 physical domains. Comparison of IG and CG at 8 weeks (t2) showed significant differences in favour of IG in leg press (p=0.001), bench press (p=0.011), sit-to-stand (p=0.001) and crunch (0.006). Constipation revealed a significant difference in favour of IG at t2 (p=0.033). Quality of life stabilized/increased in IG during the study period compared to a decrease in CG. Throughout/Over the 8 weeks, fatigue notably reduced in the IG (p=0.028).
CONCLUSIONS: Exercise is safe and feasible in patients with aPBC undergoing further line therapy. Significant improvements in physical functioning and increased quality of life were achieved. German Clinical Trials Register ID: DRKS00021179; Registration date 15.05.2020.

Under optimal physiological conditions, muscle mass maintenance is ensured by dietary protein, which balances the amino acid loss during the post-absorption period and preserves the body\'s protein homeostasis. Conversely, in critical clinical conditions (acute, subacute or postacute), particularly those related to hypomobility or immobility, combined with malnutrition, and local/systemic inflammation, the loss of muscle mass and strength can be quantitatively significant. A decline of more than 1% in muscle mass and of more than 3% in muscle strength has been registered in subjects with aged 20-37 yr after just five days of bed rest, similarly to those observed during one year of age-related decline in individuals over the age of 50. Loss of muscle mass and strength can have a dramatic effect on subjects\' functional capacities, on their systemic metabolic control and on the amino acid reserve function, all of which are fundamental for the maintenance of other organs\' and tissues\' cell processes. References available indicate that the average 1%-2% reduction per day of muscle mass in patients in the intensive care unit (ICU) could represent an independent predictor of hospital mortality and physical disability in the five years following hospitalization. After just a few days or weeks of administration, supplementation with EAAs and glutamine has shown significant effects in maintaining muscle size and strength, which are typically negatively affected by some acute/subacute or postacute critical conditions (muscle recovery after surgery, oncology patients, ICU treatments), especially in the elderly or in those with pre-existing degenerative diseases. In this review, we focused on the theoretical bases and the most relevant clinical studies of EAA and glutamine supplementation as a single compound, with the aim of clarifying whether their combined use in a blend (EAAs-glutamine) could be potentially synergistic to prevent disease-related muscle wasting and its impact on the duration and quality of patients\' clinical course.

Cancer cachexia is a multifactorial condition that contributes to the death of about 20% of cancer patients. It has the potential to cause weight loss, reduction in muscle mass, and loss of fat tissue, significantly lowering the quality of life. Currently, there are no approved drugs for cancer cachexia. Here, we have explored the possible impact of brassinin (BSN) on cancer cachexia under in vitro and in vivo settings. After differentiation, C2C12 and 3T3-L1 cells were incubated with colorectal carcinoma cells conditioned media or BSN. For preclinical studies, mice were injected with HT-29 cells followed by intraperitoneal administration of BSN, and muscle and adipose tissues were evaluated by Western blotting and hematoxylin and eosin staining. BSN effectively suppressed muscle atrophy by down-regulating the levels of Muscle RING-finger protein-1 and Atrogin-1, while also increasing the expression of myosin heavy chain in cachexia-induced-C2C12 myotubes. The induction of adipogenesis by BSN prevented adipocyte atrophy in cachexia-induced 3T3-L1 adipocytes. We also noted that BSN disrupted the interaction between COX-2 and signaling transducer and activator of transcription 3 (STAT3) promoter, leading to down-regulation of STAT3 activation. Moreover, it was found that BSN inhibited weight loss in mice and demonstrated anti-cachexic effects. Overall, our observations indicate that BSN can attenuate cancer cachexia through diverse mechanisms.