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Muscle cachexia is one of the most critical unmet medical needs. Identifying the molecular background of cancer-induced muscle loss revealed a promising possibility of new therapeutic targets and new drug development. In this review, we will define the signal transducer and activator of transcription 3 (STAT3) protein’s role in the tumor formation process and summarize the role of STAT3 in skeletal muscle cachexia. Finally, we will discuss a vast therapeutic potential for the STAT3-inhibiting single-agent treatment innovation that, as the desired outcome, could block tumor growth and generally prevent muscle cachexia.

Cachexia is a multifactorial syndrome characterized by severe muscle wasting and is a debilitating condition frequently associated with cancer. Previous studies from our group revealed that withaferin A (WFA), a steroidal lactone, mitigated muscle cachexia induced by ovarian tumors in NSG mice. However, it remains unclear whether WFA’s protective effects are direct or secondary to its antitumor properties. We developed a cachectic model through continuous angiotensin II (Ang II) infusion in C57BL/6 mice to address this issue. Ang II infusion resulted in profound muscle atrophy, evidenced by significant reductions in grip strength and in the TA, GA, and GF muscle mass. Molecular analyses indicated elevated expression of inflammatory cytokines (TNFα, IL-6, MIP-2, IL-18, IL-1β), NLRP3 inflammasome, and genes associated with the UPS (MuRF1, MAFBx) and autophagy pathways (Bacl1, LC3B), along with suppression of anti-inflammatory heme oxygenase-1 (HO-1) and myogenic regulators (Pax7, Myod1). Strikingly, WFA treatment reversed these pathological changes, restoring muscle mass, strength, and molecular markers to near-normal levels. These findings demonstrate that WFA exerts direct anti-cachectic effects by targeting key inflammatory and atrophic pathways in skeletal muscle, highlighting its potential as a novel therapeutic agent for cachexia management.

Background Around 80% of patients with advanced cancer have cancer cachexia (CC), a serious complication for which there are currently no FDA‐approved treatments. Nuciferine (NF) is the main active ingredient of lotus leaf, which has anti‐inflammatory, anti‐tumour and other effects. The purpose of this work was to explore the target and mechanism of NF in preventing cancer cachexia‐induced muscle atrophy. Methods The action of NF against CC‐induced muscle atrophy was determined by constructing an animal model with a series of behavioural tests, H&E staining and related markers. Network pharmacology and molecular docking were used to preliminarily determine the mechanism and targets of NF against CC‐induced muscle atrophy. The mechanisms of NF in treating CC‐induced muscle atrophy were verified by western blotting. Molecular dynamics simulation (MD), drug affinity responsive target stability (DARTS) and surface plasmon resonance (SPR) were used to validate the key target of NF. Results After 13 days of NF treatment, the reduction of limb grip strength and hanging time in LLC model mice increased by 29.7% and 192.2% (p ≤ 0.01; p ≤ 0.001). Gastrocnemius and quadriceps muscles weight/initial body weight (0.98 ± 0.11 and 1.20 ± 0.17) and cross‐sectional area of muscle fibres (600–1600 μm2) of NF‐treated mice were significantly higher than those of the model group (0.84 ± 0.10, 0.94 ± 0.09, 400–800 μm2, respectively) (p ≤ 0.01; p ≤ 0.01; p ≤ 0.001). NF treatment also decreased the MyHC (myosin heavy chain) degradation and the protein levels of muscle‐specific E3 ubiquitin ligases Atrogin1 and MuRF1 in the model group (p ≤ 0.001; p ≤ 0.01; p ≤ 0.05). Network pharmacology revealed that NF majorly targeted AKT1, TNF and HSP90AA1 to regulate PI3K‐Akt and inflammatory pathways. Molecular docking predicted that NF bound best to HSP90AA1. Mechanism analysis demonstrated that NF regulated NF‐κB and AKT–mTOR pathways for alleviating muscle wasting in tumour bearing mice. The results of MD, DARTS and SPR further confirmed that HSP90AA1 was the direct target of NF. Conclusions Overall, we first discovered that NF retards CC‐induced muscle atrophy by regulating AKT–mTOR and NF‐κB signalling pathways through directly binding HSP90AA1, suggesting that NF may be an effective treatment for cancer cachexia.

Sarcopenia (muscle wasting) and cachexia share some pathophysiological aspects. Sarcopenia affects approximately 20 %, cachexia <10 % of ambulatory patients with heart failure (HF). Whilst sarcopenia means loss of skeletal muscle mass and strength that predominantly affects postural rather than non-postural muscles, cachexia means loss of muscle and fat tissue that leads to weight loss. The wasting continuum in HF implies that skeletal muscle is lost earlier than fat tissue and may lead from sarcopenia to cachexia. Both tissues require conservation, and therapies that stop the wasting process have tremendous therapeutic appeal. The present paper reviews the pathophysiology of muscle and fat wasting in HF and discusses potential treatments, including exercise training, appetite stimulants, essential amino acids, growth hormone, testosterone, electrical muscle stimulation, ghrelin and its analogues, ghrelin receptor agonists and myostatin antibodies.

A single injection of low-dose human umbilical cord-derived mesenchymal stem cells (UC-MSCs) has been previously demonstrated to relieve synovitis and bone erosion in animal models of arthritis, but whether frequent injections of high-dose UC-MSCs relieve arthritis and inhibit loss of muscle mass has remained elusive. In the present study, DBA/1 mice were randomly divided into three groups: Normal (wild-type mice; n=11), collagen-induced arthritis (CIA; n=12) and CIA treated with UC-MSCs (n=11; 5x106 UC-MSCs per week for 3 weeks). Arthritis and skeletal muscle cachexia were evaluated until the end of the experiment on day 84. It was indicated that both the CIA and UC-MSC groups had lower body weights compared with the normal mice. Clinical arthritis scores, hind ankle diameters, synovitis and bone erosion progressively increased and were similar between the CIA and UC-MSC groups. Although there was no difference in food intake among the three groups, the normalized food intake of normal group was significantly higher than CIA group and UC-MSC group from day 42 onwards; there was no significance on day 77 but this could be neglected. Furthermore, gastrocnemius muscle weight in the UC-MSC group was significantly reduced compared with that in the CIA and normal groups. The UC-MSC group had higher levels of proinflammatory cytokines, such as TNF-α, IL-6 and IL-1β than those in the CIA group. However, the other cytokines assessed and the fibrosis indices in the CIA and UC-MSC groups were not different from those in the control group and there was no inflammatory cell infiltration. Thus, frequent injections of high-dose UC-MSCs slightly aggravated synovitis and muscle cachexia in the murine CIA model and should therefore be avoided in the treatment of arthritis.

Cachexia presents with ongoing muscle wasting, altering quality of life in cancer patients. Cachexia is a limiting prognostic factor for patient survival and health care costs. Although animal models and human trials have shown mechanisms of motorprotein proteolysis, not much is known about intrinsic changes of muscle functionality in cancer patients suffering from muscle cachexia, and deeper insights into cachexia pathology in humans are needed. To address this question, rectus abdominis muscle samples were collected from several surgical control, non‐cachectic and cachectic cancer patients and processed for skinned fibre biomechanics, molecular in vitro motility assays, myosin isoform protein compositions and quantitative ubiquitin polymer protein analysis. In pre‐cachectic and cachectic cancer patient samples, maximum force was significantly compromised compared with controls, but showed an unexpected increase in myofibrillar Ca2+ sensitivity consistent with a shift from slow to fast myosin isoform expression seen in SDS‐PAGE analysis and in vitro motility assays. Force deficit was specific for ‘cancer’, but not linked to presence of cachexia. Interestingly, quantitative ubiquitin immunoassays revealed no major changes in static ubiquitin polymer protein profiles, whether cachexia was present or not and were shown to mirror profiles in control patients. Our study on muscle function in cachectic patients shows that abdominal wall skeletal muscle in cancer cachexia shows signs of weakness that can be partially attributed to intrinsic changes to contractile motorprotein function. On protein levels, static ubiquitin polymeric distributions were unaltered, pointing towards evenly up‐regulated ubiquitin protein turnover with respect to ubiquitin conjugation, proteasome degradation and de‐ubiquitination.

The first reports of accurate skeletal muscle mass measurement in human subjects appeared at about the same time as introduction of the sarcopenia concept in the late 1980s. Since then these methods, computed tomography and MRI, have been used to gain insights into older (i.e. anthropometry and urinary markers) and more recently developed and refined methods (ultrasound, bioimpedance analysis and dual-energy X-ray absorptiometry) of quantifying regional and total body skeletal muscle mass. The objective of this review is to describe the evolution of these methods and their continued development in the context of sarcopenia evaluation and treatment. Advances in these technologies are described with a focus on additional quantifiable measures that relate to muscle composition and ‘quality’. The integration of these collective evaluations with strength and physical performance indices is highlighted with linkages to evaluation of sarcopenia and the spectrum of related disorders such as sarcopenic obesity, cachexia and frailty. Our findings show that currently available methods and those in development are capable of non-invasively extending measures from solely ‘mass’ to quality evaluations that promise to close the gaps now recognised between skeletal muscle mass and muscle function, morbidity and mortality. As the largest tissue compartment in most adults, skeletal muscle mass and aspects of muscle composition can now be evaluated by a wide array of technologies that provide important new research and clinical opportunities aligned with the growing interest in the spectrum of conditions associated with sarcopenia.

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.

Skeletal muscle loss and dysfunction in aging and chronic diseases is one of the major causes of mortality in patients, and is relevant for a wide variety of diseases such as neurodegeneration and cancer. Muscle loss is accompanied by changes in gene expression and metabolism that lead to contractile impairment and likely affect whole-body metabolism and function. The changes may be caused by inactivity, inflammation, age-related factors or unbalanced nutrition. Although links with skeletal muscle loss have been found in diseases with disparate aetiologies, for example both in Huntington’s disease (HD) and cancer cachexia, the outcome is a similar impairment and mortality. This short commentary aims to summarize recent achievements in the identification of common mechanisms leading to the skeletal muscle wasting syndrome seen in diseases as different as cancer and HD. The latter is the most common hereditary neurodegenerative disorder and muscle wasting is an important component of its pathology. In addition, possible therapeutic strategies for anti-cachectic treatment will be also discussed in the light of their translation into possible therapeutic approaches for HD.

This paper reviews the health implications of obesity, sarcopenia and sarcopenic obesity on CVD and mortality in older adults and discusses the obesity paradox seen in patients with CVD. Obesity is a major public health problem with increasing prevalence worldwide. It is an established risk factor for cardiovascular morbidity and mortality in adult populations. However, there is controversy surrounding the effects of obesity as measured by BMI in older people, and overweight and obesity (BMI ⩾ 25 kg/m2) are apparently associated with increased survival in those with CVD (obesity paradox). Ageing is associated with an increase in visceral fat and a progressive loss of muscle mass which have opposing effects on mortality. Thus BMI is not a good indicator of obesity in older adults. Sarcopenia, the age-associated loss of skeletal muscle mass, is a major concern in ageing populations and has been associated with metabolic impairment, CVD risk factors, physical disability and mortality. Sarcopenia often coexists with obesity. Sarcopenic obesity is a new category of obesity in older adults who have high adiposity coupled with low muscle mass. To fully understand the effect of obesity on mortality in the elderly it is important to take muscle mass into account. The evidence suggests that sarcopenia with obesity may be associated with higher levels of metabolic disorders and an increased risk of mortality than obesity or sarcopenia alone. Efforts to promote healthy ageing should focus on both preventing obesity and maintaining or increasing muscle mass.