PP032 - GUT BACTEROIDES MEDIATES ARGININE RESCUE OF CANCER- RELATED SARCOPENIA VIA ENDOPLASMIC RETICULUM STRESS RESOLUTION

PP032

GUT BACTEROIDES MEDIATES ARGININE RESCUE OF CANCER- RELATED SARCOPENIA VIA ENDOPLASMIC RETICULUM STRESS RESOLUTION

X. Liu¹, W. Yang¹, Y. Liu¹, Y. Zhao¹, J. Cui^1,*

¹The First Hospital of Jilin University, Changchun, China

Rationale: Cancer-related sarcopenia is a debilitating syndrome characterized by progressive muscle wasting and metabolic dysregulation. This study aimed to elucidate the role of arginine metabolism in tumor-induced muscle atrophy and investigate whether the gut microbiota modulates the therapeutic response to arginine supplementation.

Methods: We utilized the Lewis Lung Carcinoma mouse model to induce sarcopenia. Muscle atrophy was assessed by wet weight, grip strength, and histological analysis. Untargeted metabolomics and 16S rRNA sequencing were performed to profile metabolic and microbial alterations. We engineered C2C12 expressing a VHL-mcherry fusion reporter to monitor endoplasmic reticulum (ER) stress markers and myogenic factors. Samples from sarcopenic cancer patients receiving arginine supplementation were analyzed to validate preclinical findings.

Results: This study established a cancer-related sarcopenia model. Tumor-bearing mice exhibited severe arginine depletion compared to the control group (p<0.001). This arginine starvation triggered ER stress in skeletal muscle, characterized by the accumulation of unfolded proteins and significant upregulation of the Bip/IRE1α pathway, leading to suppressed myogenesis and atrophy. Arginine supplementation effectively restored muscle mass and function in a dose-dependent manner (0, 1.5, and 3 g/kg/day) (p<0.05). However, antibiotic-induced dysbiosis completely abolished these protective effects. Microbiome analysis revealed that arginine treatment enriched Akkermansia and Bacteroides. 

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Conclusion: Our findings establish a critical "Gut-Metabolite-Muscle" axis wherein tumor-induced arginine deprivation disrupts muscle proteostasis via ER stress. These results support a "Precision Synbiotic Strategy" for managing Cancer-related sarcopenia, integrating microbiome modulation to optimize nutritional therapy.

Disclosure of Interest: None declared