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Association between elevated expression of GDF15/GFRAL and sarcopenia risk

ABSTRACT: Glial cell line-derived neurotrophic factor family receptor α-like (GFRAL) is the exclusive receptor for growth differentiation factor 15 (GDF15) and plays distinct roles in various diseases. However, its impact on sarcopenia remains poorly understood. This study, comprising participants of White British and Chinese descent, demonstrated that elevated serum levels of GDF15 and its receptor GFRAL are associated with an increased risk of sarcopenia, particularly among individuals with low physical performance. While GDF15 exerts effects across the whole population, GFRAL appears to be more detrimental in women. Complementary single-cell RNA sequencing and immunohistochemical analyses in animal models further support the involvement of the GDF15–GFRAL axis in mediating skeletal muscle damage. These findings highlight the clinical and preventive relevance of the GDF15–GFRAL axis and underscore the need for future mechanistic studies to elucidate its role in sarcopenia.

ORGANISM(S): Mus musculus

PROVIDER: GSE316316 | GEO | 2026/03/11

REPOSITORIES: GEO

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Project description:Elevation of growth differentiation factor 15 (GDF15) has recently emerged as a key driver of cancer cachexia, a syndrome of extreme weight loss that affects patients with various types of cancer. Chemotherapy, as well as the tumour itself have been reported to contribute to increased GDF15 secretion in both cancer and host tissues. Bromodomain and extraterminal (BET) domain proteins have been shown to regulate GDF15 expression in pancreatic cancer cells. With currently neither preventive strategies nor specific therapeutic options for cachexia available, antibodies targeting GDF15 or its receptor are being developed. However, the mechanism of chemotherapy-induced GDF15 upregulation in tumour and host cells is still unknown, leaving uncertainty about safety and efficacy of therapies targeting retrospective reduction of GDF15 in cancer cachexia. We tested various cardiotoxic drugs for their effect on GDF15 regulation in cardiomyocyte cell culture and analysed gene expression, mutational status, and pathway activities of the NCI-60 cancer cell line panels to get further insights into the regulation of GDF15 expression in both cancer and host cells upon treatment with anticancer drugs. To investigate the regulatory effect of BET inhibition on GDF expression more extensively, we screened BET inhibitors in doxorubicin treated human cardiomyocyte cell culture as well as in 21 cancer cell lines and performed differential analysis of gene expression, metabolites, and pathway activities. Our results reveal that DNA interacting compounds induce GDF15 expression in human cardiomyocytes up to 20-fold, whereas cardiotoxic drugs with other modes of action led, if at all, to less than 3-fold induction. We discovered that BET inhibitors suppress doxorubicin-induced GDF15 overexpression in human cardiomyocytes up to 7.4-fold (p=0.0051). In cancer cell lines, we identified compound-specific gene signatures that correlate with the extent of GDF15 induction upon treatment in the espective cell line. BET inhibition also reduces GDF15 expression in a defined subset of cancer cell lines that differentiate from the other tested cell lines in a less active PI3K/Akt axis and significantly higher extracellular pantothenate concentration (p=0.00095). We identified compound- and cell-line-specific gene signatures that predict GDF15 upregulation upon treatment, providing indication that the risk for drug-induced GDF15 overexpression and concomitant cachexia can be reduced by a biomarker-driven selection of patient-specific anticancer agents. Our results suggest that BET inhibitors could counteract cachexia at the transcriptional level in tumour and host tissues by reducing GDF15 expression. We identified characteristic gene and metabolite expressions of responsive cancer cell lines that can serve as biomarkers for patient selection.

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Association between elevated expression of GDF15/GFRAL and sarcopenia risk

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