The autophagic-lysosomal and ubiquitin proteasome systems are simultaneously activated in the skeletal muscle of gastric cancer patients with cachexia

Abstract

Background Cancer cachexia is characterized by weight loss, especially ongoing skeletal muscle loss, and is associated with poor patient outcomes. However, the molecular mechanism of skeletal muscle wasting is not fully understood. Objectives We aimed to investigate muscle fiber morphology and proteolysis system activity changes that may account for cancer cachexia and to relate these changes to patients’ clinical phenotypes. Methods We divided 39 patients with resectable gastric cancer into 4 groups based on the presence of cachexia (weight loss) and/or sarcopenia (low muscularity), including a noncachexia/nonsarcopenia group (N, n = 10), a cachexia/sarcopenia group (CS, n = 13), a cachexia/nonsarcopenia group (C, n = 9), and a noncachexia/sarcopenia group (S, n = 7). Rectus abdominis muscle biopsy specimens were obtained intraoperatively. Muscle fiber size, ultrastructural architecture, and the expression of autophagic-lysosomal system (ALS) and ubiquitin proteasome system (UPS) markers were assayed. Results Mean ± SD muscle fiber cross-sectional areas were significantly decreased in the CS (460 ± 120 μm2) and S groups (480 ± 135 μm2) compared with the N (1615 ± 388 μm2, both P < 0.05) and C groups (1219 ± 302 μm2, both P < 0.05). In the C, S, and CS groups, the muscle exhibited tissue disorganization and autophagosome formation to different degrees. The levels of ALS and UPS markers were significantly increased in the CS, C, and S groups compared with the N group. Alterations in muscle fiber morphology and increased ALS and UPS activity were related to severe muscle loss, but not weight loss. Conclusions The ALS and UPS are simultaneously activated in cancer cachexia and may play coordinated roles in cachexia-induced muscle loss.

Cancer cachexia and skeletal muscle atrophy in clinical studies: what do we really know?

“…cofilin, dystonin, and vinculin) in pancreatic cancer patients. 50 While a significant reduction in the cross-sectional area of muscle fibres was observed in gastrointestinal cancer patients with cachexia and muscle loss, 46,51 Op den Kamp et al found no such change in cachectic patients with advanced non-small-cell lung cancer compared with pre-cachectic patients. 52 Finally, no significant alteration in fibre typing associated with cancer cachexia has been reported in clinical studies, either of gastrointestinal 51,53 or lung 54 cancer.…”

“…45 Skeletal muscle ultrastructure also appears to be impaired, with an apparent disorganization and autophagosome formation in gastric cancer patients with cachexia. 46 The protein expression of myosin heavy chains, a major component of the muscular contractile system, was increased (for isoforms 1, 4, and 8), 47 decreased, 48 or unchanged 49 in cachectic patients with gastrointestinal cancer. Other muscular structural components have also been studied.…”

“…[85][86][87][88] However, results from clinical studies are much more controversial ( Table 1). Some studies have reported an increased expression of autophagy markers (Beclin-1, LC3B, ATG5, ATG7, and p62) 46,51,55,57 and of UPS proteins (MuRF1 and polyubiquitinylated proteins), 46 as well as muscle atrophy-inducing pathway regulators (SMAD3) 51 in cachectic patients with mainly gastrointestinal cancer. Increased proteasome activity in gastric cancer 58 and increased protein expression of proteasome 20S subunits in colorectal and pancreatic cancers 59 were also reported.…”

“…cofilin, dystonin, and vinculin) in pancreatic cancer patients 50 . While a significant reduction in the cross‐sectional area of muscle fibres was observed in gastrointestinal cancer patients with cachexia and muscle loss, 46,51 Op den Kamp et al . found no such change in cachectic patients with advanced non‐small‐cell lung cancer compared with pre‐cachectic patients 52 .…”

The differentiation of hematopoietic stem cells was reprogrammed in advanced tumor-bearing mice

“…As a fatal, polyfactorial, and irreversible syndrome, cachexia affects about 50-80% of patients with various types of tumors [3] . Cancer cachexia has been defined by an international consensus as a multifactorial syndrome including loss of weight, muscle atrophy, weakness, anorexia, fatigue, low immunity and severe hematopoietic abnormalities [4][5][6][7] . It is well accepted to concentrates on cachexia as a metabolic disorder.…”