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.

Keywords: autophagy; cancer cachexia; gastric cancer; lysosome; muscle wasting; proteasome; ubiquitin.