Cancer-induced cachexia has a negative impact on quality of life and adversely affects therapeutic outcomes and survival rates. It is characterized by, often severe, loss of muscle, with or without loss of fat mass. Insight in the pathophysiology of this complex metabolic syndrome and direct treatment options are still limited, which creates a research demand. Results from recent studies point towards a significant involvement of muscle mitochondrial networks. However, data are scattered and a comprehensive overview is lacking. This paper aims to fill existing knowledge gaps by integrating published data sets on muscle protein or gene expression from cancer-induced cachexia animal models. To this end, a database was compiled from 94 research papers, comprising 11 different rodent models. This was combined with four genome-wide transcriptome datasets of cancer-induced cachexia rodent models. Analysis showed that the expression of genes involved in mitochondrial fusion, fission, ATP production and mitochondrial density is decreased, while that of genes involved ROS detoxification and mitophagy is increased. Our results underline the relevance of including post-translational modifications of key proteins involved in mitochondrial functioning in future studies on cancer-induced cachexia.

Muscle wasting is a frequently observed, inflammation-driven condition in aging and disease, known as sarcopenia and cachexia. Current treatment strategies target the muscle directly and are often not able to reverse the process. Because a reduced gut function is related to systemic inflammation, this might be an indirect target to ameliorate muscle wasting, by administering pro-, pre-, and synbiotics. Therefore, this review aimed to study the potential of pro-, pre-, and synbiotics to treat muscle wasting and to elucidate which metabolites and mechanisms affect the organ crosstalk in cachexia. Overall, the literature shows that Lactobacillus species pluralis (spp.) and possibly other genera, such as Bifidobacterium, can ameliorate muscle wasting in mouse models. The beneficial effects of Lactobacillus spp. supplementation may be attributed to its potential to improve microbiome balance and to its reported capacity to reduce gut permeability. A subsequent literature search revealed that the reduction of a high gut permeability coincided with improved muscle mass or strength, which shows an association between gut permeability and muscle mass. A possible working mechanism is proposed, involving lactate, butyrate, and reduced inflammation in gut–brain–muscle crosstalk. Thus, reducing gut permeability via Lactobacillus spp. supplementation could be a potential treatment strategy for muscle wasting.

Achieving weight loss is the cornerstone of the treatment of the metabolic consequences of obesity, in particular of glucose intolerance. To determine whether improvement in glucose control depends on dietary macronutrient composition of the diet at identical weight loss. Twenty-two weeks old diet-induced obese C57BL/6 mice lost weight through caloric restriction on normal chow (R-NC) or high fat diet (R-HF). Control mice were fed normal chow (LEAN) or high fat diet (OBESE) ad libitum. Body weight and composition were assessed after 8 weeks of dietary intervention. Glucose homeostasis was evaluated by intraperitoneal glucose tolerance tests (IPGTT). Epididymal white adipose (eWAT) and hepatic tissues were analyzed by immunohistochemistry and RT-qPCR. By 30 weeks of age, the body weight of the mice on R-NC (31.6±1.7g, mean±SEM) and R-HF (32.3±0.9g) was similar to LEAN mice (31.9±1.4g), while OBESE mice weighed 51.7±2.4g. Glucose tolerance in R-NC was better than in LEAN mice (69% AUC IPGTT, P 0.0168) whereas R-HF mice remained significantly less glucose tolerant (125% AUC IPGTT, P 0.0279 vs LEAN), despite identical weight loss. The eWAT pads and adipocyte size were similar in LEAN and R-NC mice, while the eWAT pad size of R-HF was 180% of R-NC (P < 0.0001) and the average adipocyte size of R-HF mice was 134% of R-NC fed mice (P 0.0285). No LEAN or R-NC mice had hepatic steatosis, in contrast to 28.6% of R-HF mice. Compared to OBESE mice, inflammatory markers were lower in eWAT and liver tissue of R-NC, but not in R-HF mice. Measures of visceral adiposity correlated well with glucose tolerance parameters. In mice, caloric restriction on a normal chow diet improved glucose tolerance significantly more when identical weight loss was achieved on a high fat diet.

Targeted exercise combined with nutritional and pharmacological strategies is commonly considered to be the most optimal strategy to reduce the development and progression of cachexia. For COPD patients, this multi-targeted treatment has shown beneficial effects. However, in many, physical activity is seriously hampered by frailty and fatigue. In the present study, effects of whole-body-vibration-training (WBV) were investigated, as potential alternative to active exercise, on body mass, muscle mass and function in tumour bearing mice. Twenty-four male CD2F1-mice (6–8 weeks, 21.5 ± 0.2 g) were stratified into four groups: control, control + WBV, C26 tumour-bearing, and C26 tumour-bearing + WBV. From day 1, whole-body-vibration was daily performed for 19 days (15 min, 45 Hz, 1.0 g acceleration). General outcome measures included body mass and composition, daily activity, blood analysis, assessments of muscle histology, function, and whole genome gene expression in m. soleus (SOL), m. extensor digitorum longus (EDL), and heart. Body mass, lean and fat mass and EDL mass were all lower in tumour bearing mice compared to controls. Except from improved contractility in SOL, no effects of vibration training were found on cachexia related general outcomes in control or tumour groups, as PCA analysis did not result in a distinction between corresponding groups. However, analysis of transcriptome data clearly revealed a distinction between tumour and trained tumour groups. WBV reduced the tumour-related effects on muscle gene expression in EDL, SOL and heart. Gene Set Enrichment Analysis showed that these effects were associated with attenuation of the upregulation of the proteasome pathway in SOL. These data suggest that WBV had minor effects on cachexia related general outcomes in the present experimental set-up, while muscle transcriptome showed changes associated with positive effects. This calls for follow-up studies applying longer treatment periods of WBV as component of a multiple-target intervention.