ABSTRACT Background Cancer cachexia is associated with rapid body wasting and cardiac dysfunction. Bisoprolol (BIS) and megestrol acetate (MA) improve selected cachexia phenotypes in the Yoshida AH‐130 model, but their combined effects are not defined. We tested reduced‐dose combined treatment of BIS and MA (COMB) on survival and organ‐specific outcomes. Methods Male Wistar Han rats (approx. 200 g) received intraperitoneal Yoshida AH‐130 hepatoma cells and were treated with placebo (PL, n = 49), BIS (5 mg/kg/day, n = 23), MA (100 mg/kg/day, n = 10) or COMB (BIS 3.75 mg/kg/day + MA 75 mg/kg/day, n = 16). Outcomes included survival, echocardiography (baseline and Day 11), body composition (EchoMRI), terminal tissue weights, food intake and spontaneous locomotor activity. Results COMB reduced mortality versus placebo (HR = 0.21, p < 0.0001) and had the lowest HR among treatment groups. BIS also reduced mortality versus PL (HR = 0.32, p = 0.0007), whereas MA did not reach statistical significance (HR = 0.49, p = 0.082). COMB did not differ significantly from BIS (HR for COMB vs. BIS = 0.48, p = 0.28) or MA (HR for COMB vs. MA = 0.23, p = 0.06). On Day 11, COMB showed higher LVEF than PL (64.1% ± 9.7% vs. 50.5% ± 12.8%, p < 0.01), higher LV stroke volume (186 ± 49 μL vs. 112 ± 55 μL, p < 0.001) and higher LV mass (515 ± 95 mg vs. 429 ± 65 mg, p < 0.01); changes from baseline were smaller in COMB than PL for LVEF (Δ −12.0% ± 8.9% vs. −24.3% ± 16.2%, p < 0.05) and LV mass (Δ −57 ± 93 mg vs. −137 ± 79 mg, p < 0.05). Body weight, fat mass and lean mass decreased in all groups; COMB showed smaller reductions than PL (p < 0.05) but did not differ from BIS or MA (p > 0.05). BAT weight was higher in COMB than PL (p < 0.001) and higher than BIS (p < 0.001). Food intake on Day 11 was higher than PL in all active groups, and locomotor activity was higher than PL in MA and COMB. Conclusions COMB reduced mortality versus placebo and showed the lowest HR among treatment groups, accompanied by preserved cardiac performance and a distinct BAT response. Differences versus monotherapy were not statistically significant. Future studies should test optimized dosing and include exposure assessment and tissue profiling to determine benefit over monotherapy and to clarify the basis of the cardiac and BAT phenotypes.

Background: Cancer cachexia is a serious condition during the last stages of the disease, which is characterized by the loss of muscle and fat mass in patients with cancer. There are no effective treatments for cancer cachexia, and new treatment interventions are urgently needed. We have previously demonstrated that 5 mg/kg/day bisoprolol and 1.7 µg/kg/day ARA 284, a small non-erythropoietic tissue protective peptide, separately have positive effects in a rat model of cancer cachexia. Methods: We investigated the compound effects of both bisoprolol and ARA 284 by targeting multiple pathways in the Yoshida hepatoma rat model of cancer cachexia. Rats were randomly allocated to one of the following treatment groups: bisoprolol (5 mg/kg/day), ARA 284 (1.7 µg/kg/day), a 25% combination (1.25 mg/kg/day bisoprolol + 0.425 µg/kg/day ARA 284), a 75% combination (3.75 mg/kg/day bisoprolol + 1.275 µg/kg/day ARA 284), or placebo. Results: The combination of 3.75 mg/kg/day bisoprolol and 1.275 µg/kg/day ARA 284 showed the strongest overall effects compared with the respective effective monotherapies, respectively, or placebo across multiple endpoints, including body weight, lean mass, food intake, spontaneous activity, and cardiac function in a rat model of cancer cachexia (p < 0.01, respectively). Furthermore, this combination therapy had the strongest effects on survival against the placebo (hazard ratio 0.08, 95% confidence interval 0.04 to 0.17, p < 0.001). Conclusions: Our findings show that the combination of bisoprolol and ARA 284 is beneficial in a hepatoma cachexia model and may provide greater overall effects than either monotherapy alone.

Objectives:Cachexia is a condition marked by weight loss and reduced skeletal muscle mass, with or without the loss of fat mass, commonly occurring in patients with chronic diseases such as cancer and heart failure, on a background of inflammation. Interventions that combine nutrition and exercise may offer greater benefits than either approach alone in mitigating cachexia-related impairments. Nevertheless, their overall impact remains unclear. The aim of this review was to evaluate the effectiveness of combined nutritional and exercise interventions for cachexia in patients with chronic diseases. Methods:We conducted searches via PubMed, the Cochrane Library, Embase, CINAHL, PEDro, ICTRP, and ClinicalTrials.gov through to 3 December 2024. Eligible studies were intervention studies or observational studies comparing combined nutritional and exercise interventions with control conditions, which included usual care or unimodal interventions (nutrition or exercise alone), in patients diagnosed with cachexia according to the Evans or Fearon criteria. The assessed outcomes included body weight, body composition, mortality, activities of daily living, physical function, exercise tolerance, and quality of life. Results:Of 1926 identified records, five studies involving only patients with cancer met the inclusion criteria. There is significant uncertainty regarding how combined interventions impact mortality rates compared to control groups (two studies, 66 participants: odds ratio 1.15, 95% confidence interval 0.13-9.97; I2 = 0%; evidence of very low certainty). Meta-analyses for other outcomes could not be performed because of sparse and heterogeneous data. We also identified 22 ongoing trials involving patients with cancer, chronic kidney disease, and AIDS, with results pending. Conclusions:Current evidence regarding combined nutritional and exercise interventions for cachexia is of very low certainty, and no high-quality evidence currently exists to support their effectiveness. Findings across studies are inconsistent, and further rigorous, well-designed trials are urgently needed. The development and adoption of core outcome sets will be essential to enable future meta-analyses. Results from ongoing trials are awaited.

INTRODUCTION:Cancer cachexia (CC) is a multifactorial syndrome characterized by progressive weight loss, anorexia, and loss of skeletal muscle and fat mass, resulting in reduced quality of life and poor prognosis. Currently, there are no approved pharmacological treatments for CC, highlighting the urgent need for developing novel experimental models. AREA COVERED:This review covers recent advancements in preclinical models of CC, highlighting their implications for drug discovery and therapeutic development. The literature search was conducted in PubMed up to April 2025. EXPERT OPINION:CC remains clinically challenging and requires improved translational research and therapeutic strategies. Improved preclinical models, such as personalized patient-derived xenograft models incorporating patient-specific immune profiles and microbiota, hold promise for precision medicine. Identification of standardized extracellular vesicle (EV) derived biomarkers and effective targeting of EV signaling pathways are critical research directions. In addition, clinical validation of appetite regulators such as glucagon-like peptide-1 and growth differentiation factor-15, along with comprehensive approaches integrating diet, exercise, and targeted pharmacological interventions, will be pivotal. Finally, multidisciplinary collaboration is essential to translate these findings into meaningful therapies that will ultimately improve patient prognosis and quality of life.

INTRODUCTION:Long COVID-19 illness is a severely disabling disease with shortness of breath, weakness and fatigue as leading symptoms, resulting in poor quality of life and substantial delay in return to work. No specific respiratory therapy has been validated for patients with long COVID. The intermittent hypoxia-hyperoxia training (IHHT) is a respiratory therapeutic modality to improve exercise performance via controlled respiratory conditioning. The purpose of the present study is to investigate the therapeutic effect of IHHT on functional and symptomatic recovery of patients with long COVID syndrome. METHODS:A prospective, controlled, open-treatment interventional study was conducted in patients with long COVID who were admitted to an inpatient rehabilitation programme. Patients were assigned nonrandomized to receive IHHT in addition to the standardized rehabilitation programme (IHHT group) or standard rehabilitation alone (control group). The IHHT group received supervised sessions of intermittent hypoxic (10-12% O2) and hyperoxic (30-35% O2) breathing three times per week throughout the rehabilitation period. Primary endpoint was improved walking distance in a 6-min walk test (6MWT) between study groups. Secondary endpoints were change in stair climbing power, dyspnoea (Borg dyspnoea Scale), fatigue assessment scale (FAS) and change in health-related quality of life (HRQoL) assessed by patient global assessment (PGA), EQ-5D analogue scale and the MEDIAN Corona Recovery Score (MCRS). Further assessments included maximum handgrip strength, nine hole peg test, timed up-and-go, respiratory function and functional ambulation category (FAC), serum analyses and safety of the intervention. RESULTS:A total of 145 patients were included in the study (74% female, mean age 53 ± 12 years) and assigned to IHHT (n = 70) or standard care (n = 75). The 6MWT distance improved 2.8-fold in the IHHT group compared to the control group (91.7 ± 50.1 m vs. 32.6 ± 54.2 m, ANCOVA p < 0.001). Stair climbing power improved 3.7-fold in the IHHT group compared to controls (-1.91 ± 2.23 s vs. -0.51 ± 1.93 s, p < 0.001). Secondary endpoints on dyspnoea, fatigue and HRQoL (PGA, EQ-5D and MCRS) improved significantly in the IHHT group compared to controls. The IHHT group exhibited a significant decrease in blood pressure, heart rate and increase in haemoglobin levels that was not observed in the control group. No adverse events were observed. CONCLUSION:Respiratory treatment with IHHT in addition to a multidisciplinary rehabilitation programme improves functional capacity, symptomatic status and quality of life in patients with disabling long COVID. IHHT has been demonstrated to be safe, well tolerated and feasible to be integrated in an inpatient rehabilitation programme to improve outcome in long COVID.

BACKGROUND:It is known that S-pindolol attenuates muscle loss in animal models of cancer cachexia and sarcopenia. In cancer cachexia, it also significantly reduced mortality and improved cardiac function, which is strongly compromised in cachectic animals.METHODS:Here, we tested 3 mg/kg/day of S-pindolol in two murine cancer cachexia models: pancreatic cancer cachexia (KPC) and Lewis lung carcinoma (LLC).RESULTS:Treatment of mice with 3 mg/kg/day of S-pindolol in KPC or LLC cancer cachexia models significantly attenuated the loss of body weight, including lean mass and muscle weights, leading to improved grip strength compared with placebo-treated mice. In the KPC model, treated mice lost less than half of the total weight lost by placebo (-0.9 ± 1.0 vs. -2.2 ± 1.4 g for S-pindolol and placebo, respectively, P < 0.05) and around a third of the lean mass lost by tumour-bearing controls (-0.4 ± 1.0 vs. -1.5 ± 1.5 g for S-pindolol and placebo, respectively, P < 0.05), whereas loss of fat mass was similar. In the LLC model, the gastrocnemius weight was higher in sham (108 ± 16 mg) and S-pindolol tumour-bearing (94 ± 15 mg) mice than that in placebo (83 ± 12 mg), whereas the soleus weight was only significantly higher in the S-pindolol-treated group (7.9 ± 1.7 mg) than that in placebo (6.5 ± 0.9). Grip strength was significantly improved by S-pindolol treatment (110.8 ± 16.2 vs. 93.9 ± 17.1 g for S-pindolol and placebo, respectively). A higher grip strength was observed in all groups; whereas S-pindolol-treated mice improved by 32.7 ± 18.5 g, tumour-bearing mice only show minimal improvements (7.3 ± 19.4 g, P < 0.01).CONCLUSIONS:S-pindolol is an important candidate for clinical development in the treatment of cancer cachexia that strongly attenuates loss of body weight and lean body mass. This was also seen in the weight of individual muscles and resulted in higher grip strength.

AIMS:Cachexia, a common manifestation of malignant cancer, is not only associated with weight loss, but also with severe cardiac atrophy and impaired cardiac function. Here, we investigated the effects of ACM-001 (0.3 or 3 mg/kg/day) in comparison to carvedilol (3 or 30 mg/kg/day), metropolol (50 or 100 mg/kg/day), nebivolol (1 or 10 mg/kg/day) and tertatolol (0.5 or 5 mg/kg/day) on cardiac mass and function in a rat cancer cachexia model. METHODS AND RESULTS:Young male Wistar Han rats were inoculated i.p. with 108 Yoshida hepatoma AH-130 cells and treated once daily with verum or placebo by gavage. Cardiac function (echocardiography), body weight and body composition (nuclear magnetic resonance scans) were assessed. The hearts of animals were euthanized on day 11 (placebo and 3 mg/kg/day ACM-001) were used for signalling studies. Beta-blockers had no effect on tumour burden. ACM-001 reduced body weight loss (placebo: -34 ± 2.4 g vs. 3 mg/kg/day ACM-001: -14.8 ± 8.4 g, p = 0.033). Lean mass wasting was attenuated (placebo: -16.5 ± 2.34 g vs. 3 mg/kg/day ACM-001: -2.4 ± 6.7 g, p = 0.037), while fat loss was similar (p = 0.4) on day 11. Placebo animals lost left ventricular mass (-101 ± 14 mg), which was prevented only by 3 mg/kg/day ACM-001 (7 ± 25 mg, p < 0.01 vs. placebo). ACM-001 improved the ejection fraction (EF) (ΔEF: placebo: -24.3 ± 2.6 vs. 3 mg/kg/day ACM-001: 0.1 ± 2.9, p < 0.001). Cardiac output was 50% lower in the placebo group (-41 ± 4 ml/min) compared to baseline, while 3 mg/kg/day ACM-001 preserved cardiac output (-5 ± 8 ml/min, p < 0.01). The molecular mechanisms involved inhibition of protein degradation and activation of protein synthesis pathways. CONCLUSION:This study shows that 3 mg/kg/day ACM-001 restores the anabolic/catabolic balance in cardiac muscle leading to improved function. Moreover, not all beta-blockers have similar effects.

(1) Background: Insulin resistance (IR) is a characteristic pathophysiologic feature in heart failure (HF). We tested the hypothesis that skeletal muscle metabolism is differently impaired in patients with reduced (HFrEF) vs. preserved (HFpEF) ejection fraction. (2) Methods: carbohydrate and lipid metabolism was studied in situ by intramuscular microdialysis in patients with HFrEF (59 ± 14y, NYHA I-III) and HFpEF (65 ± 10y, NYHA I-II) vs. healthy subjects of similar age during the oral glucose load (oGL); (3) Results: There were no difference in fasting serum and interstitial parameters between the groups. Blood and dialysate glucose increased significantly in HFpEF vs. HFrEF and controls upon oGT (both p < 0.0001), while insulin increased significantly in HFrEF vs. HFpEF and controls (p < 0.0005). Muscle tissue perfusion tended to be lower in HFrEF vs. HFpEF and controls after the oGL (p = 0.057). There were no differences in postprandial increases in dialysate lactate and pyruvate. Postprandial dialysate glycerol was higher in HFpEF vs. HFrEF and controls upon oGL (p = 0.0016); (4) Conclusion: A pattern of muscle glucose metabolism is distinctly different in patients with HFrEF vs. HFpEF. While postprandial IR was characterized by impaired tissue perfusion and higher compensatory insulin secretion in HFrEF, reduced muscle glucose uptake and a blunted antilipolytic effect of insulin were found in HFpEF.

AbstractBackgroundBeta‐blockers and selected stereoisomers of beta‐blockers, like bisoprolol and S‐pindolol (ACM‐001), have been shown to be effective in preclinical cancer cachexia models. Here, we tested the efficacy of stereoisomers of oxprenolol in two preclinical models of cancer cachexia—the Yoshida AH‐130 rat model and the Lewis lung carcinoma (LLC) mouse model.Methods and ResultsIn the Yoshida AH130 hepatoma rat cancer cachexia model and compared with placebo, 50 mg/kg/d S‐oxprenolol (HR: 0.49, 95% CI: 0.28–0.85, P = 0.012) was superior to 50 mg/kg/d R‐oxprenolol (HR: 0.83, 95% CI 0.38–1.45, P = 0.51) in reducing mortality (= reaching ethical endpoints). Combination of the three doses (12.5, 25 and 50 mg/kg/d) that had a significant effect on body weight loss in the S‐oxprenolol groups vs the same combination of the R‐oxprenolol groups lead to a significantly improved survival of S‐oxprenolol vs R‐oxprenolol (HR: 1.61, 95% CI: 1.08–2.39, P = 0.0185). Interestingly, there is a clear dose dependency in S‐oxprenolol‐treated (5, 12.5, 25 and 50 mg/kg/d) groups, which was not observed in groups treated with R‐oxprenolol. A dose‐dependent attenuation of weight and lean mass loss by S‐oxprenolol was seen in the Yoshida rat model, whereas R‐oxprenolol had only had a significant effect on fat mass. S‐oxprenolol also non‐significantly reduced weight loss in the LLC model and also improved muscle function (grip strength 428 ± 25 and 539 ± 37 g/100 g body weight for placebo and S‐oxprenolol, respectively). However, there was only a minor effect on quality of life indicators food intake and spontaneous activity in the Yoshida model (25 mg/kg/S‐oxprenolol: 11.9 ± 2.5 g vs placebo: 4.9 ± 0.8 g, P = 0.013 and also vs 25 mg/kg/d R‐oxprenolol: 7.5 ± 2.6 g, P = 0.025). Both enantiomers had no effects on cardiac dimensions and function at the doses used in this study. Western blotting of proteins involved in the anabolic/catabolic homoeostasis suggest that anabolic signalling is persevered (IGF‐1 receptor, Akt) and catabolic signalling is inhibited (FXBO‐10, TRAF‐6) by S‐pindolol, but not he R‐enantiomer. Expression of glucose transporters Glut1 and Glut 4 was similar in all groups, as was AMPK.ConclusionsS‐oxprenolol is superior to R‐oxprenolol in cancer cachexia animal models and shows promise for a human application in cancer cachexia.

Cachexia is associated with poor prognosis in chronic heart failure patients, but the underlying mechanisms of cachexia triggered disease progression remain poorly understood. Here, we investigate whether the dysregulation of myokine expression from wasting skeletal muscle exaggerates heart failure. RNA sequencing from wasting skeletal muscles of mice with heart failure reveals a reduced expression of Ostn , which encodes the secreted myokine Musclin, previously implicated in the enhancement of natriuretic peptide signaling. By generating skeletal muscle specific Ostn knock-out and overexpressing mice, we demonstrate that reduced skeletal muscle Musclin levels exaggerate, while its overexpression in muscle attenuates cardiac dysfunction and myocardial fibrosis during pressure overload. Mechanistically, Musclin enhances the abundance of C-type natriuretic peptide (CNP), thereby promoting cardiomyocyte contractility through protein kinase A and inhibiting fibroblast activation through protein kinase G signaling. Because we also find reduced OSTN expression in skeletal muscle of heart failure patients, augmentation of Musclin might serve as therapeutic strategy.

Interleukin-6 (IL-6) is an important player in chronic inflammation associated with heart failure and tumor-induced cachexia. Fibroblasts are salient mediators of both inflammation and fibrosis. Whereas the general outcome of IL-6 on the heart’s function and muscle wasting has been intensively studied, the influence of IL-6 on fibroblasts of the heart and skeletal muscle (SM) has not been analyzed so far. We illustrate that SM-derived fibroblasts exhibit higher basal mRNA expression of α-SMA, extracellular matrix molecules (collagen1a1/3a1/5a1), and chemokines (CCL2, CCL7, and CX3CL1) as compared to the left ventricle (LV)-derived fibroblasts. IL-6 drives the transdifferentiation of fibroblasts into myofibroblasts as indicated by an increase in α-SMA expression and upregulates NLRP3 inflammasome activity in both LV- and SM-derived fibroblasts. IL-6 increases the release of CCL7 to CX3CL1 in the supernatant of SM-derived fibroblasts associated with the attraction of more pro(Ly6Chi) versus anti(Ly6Clo) inflammatory monocytes as compared to unstimulated fibroblasts. IL-6-stimulated LV-derived fibroblasts attract less Ly6Chi to Ly6Clo monocytes compared to IL-6-stimulated SM-derived fibroblasts. In addition, SM-derived fibroblasts have a higher mitochondrial energy turnover and lower glycolytic activity versus LV-derived fibroblasts under basal and IL-6 conditions. In conclusion, IL-6 modulates the inflammatory and metabolic phenotype of LV- and SM-originated fibroblasts.

Abstract Background Cancer cachexia (CC) is a severe complication during the last stages of the disease, which is characterized by the substantial loss of muscle and fat mass. Currently, there is no effective treatment of CC. Erythropoietin plays tissue‐protective role in different tissues. Based on the structure of erythropoietin, small non‐erythropoietic peptides were synthesized, which activate tissue‐protective signalling pathways. Methods Here, we investigated the influence of the tissue‐protective peptide ARA 284 on CC in rats using the Yoshida hepatoma model. Results Treatment with ARA 284 (1.7 μg/kg/day) counteracted the loss of body weight (12.46 ± 4.82% ARA 284 vs. 26.85 ± 0.88% placebo, P < 0.01), fat mass (P < 0.01), and lean mass (P < 0.01). It improved spontaneous activity of ARA 284‐treated animals. Further, gastrocnemius mass was increased (13.2% ARA 284 vs. placebo, P < 0.01) in association with induced p‐Akt (P < 0.01) and decreased in p‐p38 MAPK, GSK‐3β, and myostatin (all P < 0.01), suggesting an induction of anabolic pathways. At the same time, we observed the significant increase in the survival of animals by high‐dose ARA 284 treatment (hazard ratio: 0.46, 95% confidence interval: 0.23–0.94, P = 0.0325). Conclusions Taken together these results suggest that ARA 284 can be considered beneficial in experimental CC and it remains to be seen, if it can have similar beneficial effects in CC patient.

The two main manifestations of wasting disorders in chronic disease are cachexia and sarcopenia. Due to sharing common pathological features, including impairments in systemic inflammation responses, neurohormonal activity, and metabolic systems, the two disorders can present with similar symptoms (tissue depletion, dyspnoea, anorexia, asthenia, fatigue, and impaired physical performance). Wasting disorders are associated with reduced quality of life and increased mortality. Cachexia is characterized by systemic tissue depletion with weight loss and sarcopenia by skeletal muscle loss accompanied by diminished muscular strength and physical performance. Wasting syndromes can be identified through clinical criteria but also through multiple imaging and diagnostic techniques. Additionally, blood biomarkers can be used for diagnosing wasting disorders. In the past decade, intensive research has focused on new therapeutic strategies within a multimodal approach, which embraces nutritional support, physical activity, and targeted pharmacological therapy. Despite some promising first therapeutic results for selected novel agents, a guideline-recommended pharmacological therapy is not yet available for cachexia or sarcopenia. More research is needed to better understand and thereby learn how to treat these wasting disorders.

Sarcopenia is primarily characterized by skeletal muscle disturbances such as loss of muscle mass, quality, strength, and physical performance. It is commonly seen in elderly patients with chronic diseases. The prevalence of sarcopenia in chronic heart failure (HF) patients amounts to up to 20% and may progress into cardiac cachexia. Muscle wasting is a strong predictor of frailty and reduced survival in HF patients. Despite many different techniques and clinical tests, there is still no broadly available gold standard for the diagnosis of sarcopenia. Resistance exercise and nutritional supplementation represent the currently most used strategies against wasting disorders. Ongoing research is investigating skeletal muscle mitochondrial dysfunction as a new possible target for pharmacological compounds. Novel agents such as synthetic ghrelin and selective androgen receptor modulators (SARMs) seem promising in counteracting muscle abnormalities but their effectiveness in HF patients has not been assessed yet. In the last decades, many advances have been accomplished but sarcopenia remains an underdiagnosed pathology and more efforts are needed to find an efficacious therapeutic plan. The purpose of this review is to illustrate the current knowledge in terms of pathogenesis, diagnosis, and treatment of sarcopenia in order to provide a better understanding of wasting disorders occurring in chronic heart failure.

Cachexia is a complex and multifactorial comorbidity characterized by a metabolic imbalance. It is defined as a body weight loss ≥5% in the last 12 months in patients with a chronic illness who also suffer from at least three of the following five symptoms: fatigue, decreased muscle strength, low fat‐free mass index, anorexia, and/or altered biochemistry (haemoglobin < 12 g/dL, serum albumin < 3.2 g/dL, increased interleukin 6, or C‐reactive protein). It is influenced by immunological, neurohormonal, and mucointestinal impairments and aggravated by factors such as malabsorption and dietary deficiencies. Cachexia is frequently seen in different chronic diseases: in 50–80% of advanced cancer patients, 30–50% of dialysis patients, 20–30% of chronic obstructive pulmonary disease patients, 20–30% of rheumatoid arthritis patients, 10% of patients after neurologic stroke, and 10–20% of chronic heart failure (CHF) patients. As an example, CHF patients share many risk factors with cachexia that also contribute to its development: high prevalence of comorbidities, immunoflammatory alterations, worsening nutritional status, and a sedentary lifestyle with a high risk for frailty due to a decrease of daily life activities or frequent rehospitalizations. Hence, wasting disorders are associated with poorer quality of life, longer hospitalization rates, and increased mortality. Therefore, there is a need for annually meetings, in person or digital, where clinicians and basic researches can share their knowledge on the topic. Over 400 participants from more than 35 countries attended the ‘12 International Conference on Cachexia, Sarcopenia and Muscle Wasting’, which was held in Berlin, Germany, from 6 to 8 December 2019. It provided a great platform for new updates about cachexia and muscle wasting disorders. Among a variety of lectures and poster presentations, one special clinical session was dedicated to the most frequent symptoms in patients with cachexia and their treatments: swallowing problems, pain, depression, muscle weakness, fatigue, and shortness of breath.

Myostatin also known as growth differentiation factor 8 (GDF-8) has been of major interest in the cachexia/sarcopenia/muscle wasting community since its discovery by McPherron et al. in 1997.1 Naturally occurring mutations leading to a faulty non-functional myostatin have been described in Belgian Blue and Piedmontese cattle as well as in whippets which show a muscle mass increase of approximately 40%.2, 3 Disturbed myostatin signalling has also been confirmed in two children, one with a homozygous mutation in the myostatin gene4 and one with a mutation in the activin receptor type-2B (ActRIIB) both leading to a vast increase in muscle mass Muscle wasting is frequently observed in the elderly population and patients with chronic diseases, in up to 50% of patients.5, 6 In several disease models of muscle wasting, an upregulation of myostatin has been shown including cancer cachexia,7-10 chemotherapy,11 kidney failure,12-15 heart failure,6 spinal muscular atrophy,16 vitamin D deficiency in infantile nephropathic cystinosis,17 glucocorticoids,14, 18 and oculopharyngeal muscular dystrophy (OPMD).19 This shows that myostatin signalling in humans is indeed a valid target for therapeutic interventions in various muscle wasting conditions. However, there seem to be a high number of translation failures in the development of myostatin targeting therapeutics. Myostatin-targeting antibodies and soluble ActRIIB to block atrophic signalling in skeletal muscle have been studied extensively in animal models and human trials with varying success. In a progeric mouse model, the soluble ActRIIB-Fc (ACE-031, Acceleron Pharma) improved muscle mass and delayed morbidity.20 In a Duchenne muscular dystrophy study, the primary endpoint of safety was met, and the study showed a trend for maintenance of the 6 min walk test, lean body mass, and bone mineral density versus placebo without reaching statistical significance.21 Atara Biotherapeutics PINTA745 showed good efficacy in a stroke mouse model, in which it attenuated loss of body weight and improved body weight recovery after cerebral ischaemia. More importantly, it also improved muscle strength and motor function.22 However, it was unsuccessful in a phase II clinical trial in renal failure, as it did not meet its primary endpoint of lean mass increase (https://www.thepharmaletter.com/article/atara-halts-development-of-pinta-745). A second monoclonal antibody—ATA 842—by Atara Biotherapeutics increased muscle mass and strength, as well as insulin sensitivity in old mice over a period of 4 weeks23 but seems to remain in the preclinical stage. Pfizer's domagrozumab (B5161002) monoclonal antibody shared the fate of showing good preclinical efficacy and failing in a phase II safety and efficacy study, where the primary endpoint of change from baseline in 4 Stair Climb following 1 year of treatment with domagrozumab as compared to placebo in patients with Duchenne's muscular dystrophy (DMD) (https://www.pfizer.com/news/press-release/press-release-detail/pfizer_terminates_domagrozumab_pf_06252616_clinical_studies_for_the_treatment_of_duchenne_muscular_dystrophy). However, in the mouse DMD mdx model, the mouse analogue of domagrozumab—mRK35—significantly increased body weight, muscle weights, grip strength, and ex vivo force production in the extensor digitorum longus (EDL) muscle.24 Domagrozumab itself dose-dependently increased lean mass and muscle volume in non-human primates.24 Eli Lilly's LY2495655 myostatin blocking antibody did not show effects on overall survival or progression-free survival and hence the trial was terminated due to imbalance in death rates between the treatment arms.25 However, in a subgroup of patients with a weight loss of less than 5%, LY2495655 show beneficial effects on muscle mass and function.25 A human dual-specific anti-ActRIIA/ActRIIB antibody [bimagrumab (BYM338)] has been developed by Novartis, which not only blocks myostatin binding but also that of activin A. The effects of bimagrumab on muscle mass and strength were greater than blocking the ActRIIA or ActRIIB alone in naïve SCID mice over a period of 4 weeks.26 In a phase II sarcopenia trial, bimagrumab treatment over 16 weeks increased muscle mass and strength in older adults and improved mobility in those with slow walking speed.27 It also improves body composition and insulin sensitivity in insulin-resistant individuals28 and accelerated recovery of muscle mass while reducing intramuscular fat in disuse atrophy induced by an immobilizing cast.29 In a small sporadic inclusion body myositis trial bimagrumab increased lean body mass and thigh muscle volume resulting in an improved 6 min walking distance.30 In this issue of the Journal of Cachexia, Sarcopenia and Muscle, Rooks et al.29 describe the safety profile, pharmacokinetics, and pharmacodynamics of the human monoclonal antibody bimagrumab, which blocks the activin type II receptors, in healthy older and obese adults. Bimagrumab was safe and well tolerated, and the pharmacokinetics were similar in both studies. A rapid increase of lean body mass and thigh muscle volume was observed, while fat mass decreased. In the high dose group (30 mg/kg, single iv. infusion), the increase of lean mass was maintained over 4 weeks, while the 3 mg/kg dose did not. Unfortunately, no improvement of muscle strength/function was observed, but this may be due to short study duration and single dosing of bimagrumab. In general, there seems to be no direct relationship between muscle mass and strength,31 making the development of myostatin pathway targeting therapeutics very challenging at best. The authors of this manuscript certify that they comply with the ethical guidelines for authorship and publishing in the Journal of Cachexia, Sarcopenia and Muscle.32 The authors have no conflict of interest regarding the subject of this editorial.

Journal of Cachexia, Sarcopenia and MuscleVolume 11, Issue 6 p. 1388-1389 EditorialOpen Access Biomarkers for cancer cachexia: where do we stand? Sandra Palus, Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, Berlin, GermanySearch for more papers by this authorJochen Springer, Corresponding Author jochen.springer@charite.de orcid.org/0000-0002-1225-0117 Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, Berlin, Germany German Centre for Cardiovascular Research (DZHK) partner site Berlin, Charité Universitätsmedizin Berlin, Berlin, Germany Correspondence to: Jochen Springer, Berlin Institute of Health Center for Regenerative Therapies (BCRT), German Centre for Cardiovascular Research (DZHK) partner site Berlin, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. Phone: +49-30-450 539403, Fax: +49-30-450 553951, Email:jochen.springer@charite.deSearch for more papers by this author Sandra Palus, Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, Berlin, GermanySearch for more papers by this authorJochen Springer, Corresponding Author jochen.springer@charite.de orcid.org/0000-0002-1225-0117 Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, Berlin, Germany German Centre for Cardiovascular Research (DZHK) partner site Berlin, Charité Universitätsmedizin Berlin, Berlin, Germany Correspondence to: Jochen Springer, Berlin Institute of Health Center for Regenerative Therapies (BCRT), German Centre for Cardiovascular Research (DZHK) partner site Berlin, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. Phone: +49-30-450 539403, Fax: +49-30-450 553951, Email:jochen.springer@charite.deSearch for more papers by this author First published: 30 November 2020 https://doi.org/10.1002/jcsm.12641AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinked InRedditWechat Cancer cachexia has been recognized as a major, life-limiting complication in the treatment of cancer patients and is composed of distinctive stages: pre-cachexia, cachexia, and refractory cachexia.1 An early diagnosis of cachexia, possibly in the pre-cachectic state, in cancer patients based on biomarkers would be extremely beneficial in the struggle to fight the multifactorial syndrome. Potential biomarker should not only be predictive but should also allow to monitor the progression of cachexia and the effects of putative therapies. However, while there are a number of biomarker candidates (for comprehensive overview, see Loumaye and Thissen2) such as TGF-β,3 activin A,4 myostatin,5, 6 systemic inflammation,7 pro-inflammatory cytokines and chemokines,8-10 micro RNAs,11-18 and protein degradation products,19-21 none have been clinically established, except for the hallmark symptom weight loss in combination with additional factors such as muscle mass and strength.22 In addition, markers of fat loss such as leptin,23, 24 free fatty acids,25, 26 glycerol,27 and zinc-α2-glycoprotein28 may be of clinical interest. In the current issue of the Journal of Cachexia, Sarcopenia and Muscle, Morigny et al. have addressed the alterations in bioactive lipids associated with cancer cachexia in pre-clinical mouse models (Colon-26, LLC, and APCMin/+) and complemented the results with the analysis of cancer patients with or without cachexia. The lipidome analysis performed by the authors included 1100 lipid species, and the results show that several bioactive lipids were regulated in cachexia. Sphingolipids (for comprehensive description of the sphingolipid metabolism, see Gault et al.29) were associated with the severity of cachexia. Most importantly, the regulation of sphingomyelin, ceramide, and hexosylceramides (16:0 and 24:1) allowed an early detection of cachexia, thus making them interesting biomarker candidates that should be validated retrospectively in material from completed clinical trials as well as in prospective clinical studies in a timely manner. Preferably, a complete analysis of the plasma lipidome should be performed, which leads to the problems of cost and availability of the (FIA)-mass spectrometry/mass spectrometry (MS/MS) platform that was utilized by the authors of this paper. However, the lack of established biomarkers that can detect pre-cachexia or early cachexia before the weight loss and/or low skeletal muscle criteria are met makes it imperative to invest heavily into the development of biomarkers like those that are discussed in the paper of Morigny et al.30 Acknowledgements The authors of this manuscript certify that they comply with the ethical guidelines for authorship and publishing in the Journal of Cachexia, Sarcopenia and Muscle.31 Conflict of interest The authors have no conflict of interest. References 1Bruggeman AR, Kamal AH, LeBlanc TW, Ma JD, Baracos VE, Roeland EJ. Cancer Cachexia: Beyond Weight Loss. J Oncol Pract. 2016; 12(11): 1163– 1171. CrossrefPubMedWeb of Science®Google Scholar 2Loumaye A, Thissen JP. Biomarkers of cancer cachexia. Clin Biochem 2017 Dec; 50: 1281– 1288. CrossrefCASPubMedWeb of Science®Google Scholar 3Lima J, Simoes E, de Castro G, Morais M, de Matos-Neto EM, Alves MJ et al. 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Introduction: Cachexia is a frequent, multifactorial syndrome associated with cancer afflicting patients' quality of life, their ability to tolerate anti-neoplastic therapies and the therapies efficacy, as well as survival. Currently, there are no approved cancer cachexia treatments other than those for the treatment of the underlying cancer. Cancer cachexia (CC) is poorly understood and hence makes clinical trial design difficult at best. This underlines the importance of well-characterized animal models to further elucidate the pathophysiology of CC and drug discovery/development. Areas covered: This review gives an overview of the available animal models and their value and limitations in translational studies. Expert opinion: Using more than one CC model to test research questions or novel compounds/treatment strategies is strongly advisable. The main reason is that models have unique signaling modalities driving cachexia that may only relate to subgroups of cancer patients. Human xenograph CC models require the use of mice with a compromised immune system, limiting their value for translational experiments. It may prove beneficial to include standard care chemotherapy in the experimental design, as many chemotherapeutic agents can induce cachexia themselves and alter the metabolic and signaling derangements of CC and thus the response to new therapeutic strategies.

Abstract Background Cachexia, a common manifestation of malignant cancer, is associated with wasting of skeletal muscle and fat tissue. In this study, we investigated the effects of a new first in class anabolic catabolic transforming agent on skeletal muscle in a rat model of cancer cachexia. Methods Young male Wistar Han rats were intraperitoneally inoculated with 108 Yoshida hepatoma AH‐130 cells and once daily treated with 0.3 mg kg−1, 3 mg kg−1 MT‐102, or placebo by gavage. Results Three mg kg−1d−1 MT‐102 not only prevented progressive loss of fat mass (−6 ± 2 g vs ‐12 ± 1 g; P < 0.001); lean mass (+1 ± 10 g vs. −37 ± 2 g; P < 0.001) and body weight (+1 ± 13 g vs. −60 ± 2 g; P < 0.001) were remained. Quality of life was also improved as indicated by a higher food intake 12.9 ± 3.1 g and 4.3 ± 0.5 g, 3 mg kg−1d−1 MT‐102 vs. placebo, respectively, P < 0.001) and a higher spontaneous activity (52 369 ± 6521 counts/24 h and 29 509 ± 1775 counts/24 h, 3 mg·kg‐1d‐1 MT‐102 vs. placebo, respectively, P < 0.01) on Day 11. Most importantly, survival was improved (HR = 0.29; 95% CI: 0.16–0.51, P < 0.001). The molecular mechanisms behind these effects involve reduction of overall protein degradation and activation of protein synthesis, assessed by measurement of proteasome and caspase‐6 activity or Western blot analysis, respectively. Conclusions The present study shows that 3 mg kg−1 MT‐102 reduces catabolism, while inducing anabolism in skeletal muscle leading to an improved survival.

AbstractBackgroundMedroxyprogesterone and megestrol acetate are synthetic progesterone derivatives. Progestagen is an approved drug for cancer cachexia in the USA and in some European countries. These agents have been described to increase appetite and to lead to weight gain. However, the effects on survival are still unknown. The aim of this study was to evaluate the effects of progesterone on survival, cardiac function, and appetite and body weight in the Yoshida hepatoma AH‐130 rat cancer cachexia model.Methods and ResultsIn this study, the effects of progesterone were tested in cachectic tumour‐bearing rats. Rats were treated with 0.5, 5 or 50 mg/kg/day, respectively, or placebo daily, starting 1 day after tumour inoculation for a period of 16 days. Cardiac function was analysed by echocardiography at baseline and at day 11. Food intake was assessed before tumour inoculation and at day 11. Body weight and body composition were evaluated at the beginning and the end of study or the day of euthanasia. Survival was significantly improved by 5 mg/kg/day (hazard ratio: 0.48, 95% confidence interval: 0.24–0.95, P = 0.0356). However, there was no significant difference between the progesterone treatment groups compared with placebo in body weight change and body composition, as well as food intake on day 11. Cardiac function also showed no significant difference compared with placebo.ConclusionsProgesterone improves survival but has no beneficial effects on cardiac function, body weight, and food intake in this aggressive hepatoma cancer cachexia rat model. Further studies are needed to elucidate the mechanism of the survival benefit.