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Dietary supplementation with ursolic acid preserves skeletal muscle mass and strength in mouse models of cancer cachexia [RNA-seq]

ABSTRACT: Skeletal muscle atrophy is a devastating and defining feature of cancer cachexia that reduces quality of life, treatment tolerance, and survival, but cannot be prevented or reversed by current management strategies. Ursolic acid is a natural dietary compound that has been shown to inhibit atrophy-associated changes in skeletal muscle mRNA expression in rodents and dogs, leading to beneficial changes in skeletal muscle structure and function. We hypothesized that dietary supplementation with ursolic acid might help support skeletal muscle mass and function during cancer. To test this hypothesis, we investigated ursolic acid's effects in five in vivo mouse models of cancer cachexia that are driven by pancreatic, colon, and lung cancer cells of mouse and human origin. We found that dietary supplementation with ursolic acid has broad-spectrum effects towards cancer-induced skeletal muscle atrophy, significantly preserving muscle mass in all five cancer cachexia models. Ursolic acid's positive effects on muscle mass and muscle fiber size led to significant improvements in grip strength and muscle tetanic force, persisted in the presence of chemotherapy, and were not associated with discernable changes in food intake or tumor growth. Ursolic acid appeared to generate its beneficial effects in skeletal muscle by acting directly on muscle cells, inhibiting catabolic effects of tumor-derived secreted factors, and inhibiting > 90% of cancer-induced changes in skeletal muscle mRNA expression. These results strongly nominate ursolic acid as a promising potential nutritional approach for supporting muscle mass and function in individuals with cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE325158 | GEO | 2026/05/05

REPOSITORIES: GEO

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Project description:Background Loss of skeletal muscle mass in advanced cancer is recognized as an independent predictor of mortality. Mechanisms involved in this wasting process and parameters for early diagnosis are still lacking. As skeletal muscle is considered as a secretory organ, the aim of this present experimental work was to characterize the changes in muscle proteome and secretome associated with cancer-induced cachexia to better understand cellular mechanisms involved in this wasting process and to identify secreted proteins which might reflect the ongoing muscle atrophy process. Methods We investigated first the changes in the muscle proteome associated with cancer-induced cachexia by using differential label-free proteomic analysis on muscle of the C26 mouse model. The differentially abundant proteins were submitted to sequential bioinformatic secretomic analysis in order to identify potentially secreted proteins. Selected reaction monitoring and Western blotting were used to verify the presence of candidate proteins at the circulating level. Their muscle source was demonstrated by assessing their gene expression in skeletal muscle and in cultured myotubes. Finally, we also investigated their regulation in muscle cells. Alterations in several molecular pathways potentially involved in muscle atrophy were highlighted using Gene ontology enrichment analyses. Results Our results revealed a dramatic increased production (2-to 25-fold) by the muscle of several acute phase reactants (APR: Haptoglobin, Serpina3n, Complement C3, Serum amyloid A1) which are also released in the circulation during C26 cancer cachexia. Their production was confirmed in other preclinical models of cancer cachexia as well as in cancer patients. The muscular origin of these APR was demonstrated by their increased expression in skeletal muscle and myotubes. Glucocorticoids and pro-inflammatory cytokines contribute directly to their increased expression in muscle cells in vitro, while the role of IL-6 in the muscular induction of these APR was demonstrated in vivo. Conclusions Cancer is associated with marked changes in muscle secretome during muscle wasting. Our study demonstrates a marked increased production of APR by skeletal muscle in pre-clinical models of cancer cachexia and in cancer patients. Further studies are required to unravel the potential role of these proteins in muscle atrophy and their interest as biomarkers of cancer cachexia.

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Dietary supplementation with ursolic acid preserves skeletal muscle mass and strength in mouse models of cancer cachexia [RNA-seq]

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