Dataset Information

Haptoglobin and glutamine synthetase as potential biomarkers of chemotherapy-induced cachexia in skeletal muscle

ABSTRACT: Cancer cachexia is a multifactorial wasting syndrome affecting body and lean tissue mass that is often exacerbated by anticancer chemotherapy. In this study, we used a mouse model of acute myeloid leukemia chemotherapy induction regimen (CIR) comprising daunorubicin and cytarabine to investigate the molecular mechanisms underlying cachexia. Quantitative tandem mass tag (TMT) based proteomics was performed on skeletal muscle (quadriceps) to uncover biomarkers and pathways associated with chemotherapy induced muscle wasting. Our findings demonstrate that the AML CIR induced an acute cachexic phenotype characterized by approximately 10 percent body and lean mass loss and 20 percent muscle fibre atrophy. Through deep proteome profiling, two potential biomarkers—haptoglobin (Hp) and glutamine synthetase (Glul)—were identified. Haptoglobin in particular was responsive to cachexia severity, recovery, and exacerbation via exercise, indicating its potential as a conditionally sensitive biomarker of muscle wasting. Pathway analysis revealed upregulation of mitochondrial metabolism including branched chain amino acid catabolism and mitochondrial uncoupling proteins (Ucp1 and Ucp3), suggesting hypermetabolism as a key driver of the phenotype. These data support the use of skeletal muscle proteomics in characterizing chemotherapy induced cachexia and identifying sensitive muscle specific biomarkers for future translational and therapeutic studies.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Skeletal Muscle

SUBMITTER: Joel Steele

LAB HEAD: Dr. Emma Rybalka

PROVIDER: PXD063910 | Pride | 2025-06-16

REPOSITORIES: Pride

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			Action	DRS
	ECPJS20230607_P23_0619_E1_LukeF_TMT_CompleteDCstudy_.xlsx	Xlsx
	ECPJS20230607_P23_0619_E1_LukeF_TMT_Complete_Peptides_DC_Study.xlsx	Xlsx
	ECPJS20230607_P23_0619_E1_LukeF_TMT_Plex1_F01.raw	Raw
	ECPJS20230607_P23_0619_E1_LukeF_TMT_Plex1_F02.raw	Raw
	ECPJS20230607_P23_0619_E1_LukeF_TMT_Plex1_F03.raw	Raw

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Publications

Haptoglobin and Glutamine Synthetase May Biomark Cachexia Induced by Antiacute Myeloid Leukaemia Chemotherapy.

Campelj Dean G DG Timpani Cara A CA Spiesberger Guinevere G Formosa Luke E LE Steele Joel R JR Zhang Haijian H Schittenhelm Ralf B RB Leow Lewis L Goodman Craig A CA Rybalka Emma E

Journal of cachexia, sarcopenia and muscle 20250601 3

<h4>Background</h4>Anticancer chemotherapy is an underappreciated contributor to cancer cachexia, an often-irreversible body-wasting condition that causes 20%-30% of cancer-related deaths. An obstacle to predicting, monitoring and understanding the mechanisms underlying chemotherapy cachexia is that each cancer (and subtype) is assigned different chemotherapeutic compounds, typically in multiagent regimens. Here, we investigate the chemotherapy induction regimen (CIR) used in the haematological ...[more]

PMID: 40468964

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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.

Project description:Background Loss of skeletal muscle mass in cancer cachexia is recognized as an independent predictor of mortality. Mechanisms involved in this wasting process and parameters for early diagnosis are not yet clearly defined. As skeletal muscle is considered as a secretory organ, the aim of this present experimental work was to characterize the changes in the putative muscle secretome associated with cancer-induced cachexia to gain a better understanding of cellular mechanisms involved and to identify secreted proteins which might reflect this wasting 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 then submitted to sequential bioinformatic secretomic analysis in order to identify potentially secreted proteins. Multiple reaction monitoring and Western blotting were used to verify the presence of candidate proteins at the circulating level. Finally, we investigated the regulation of the production of these secreted proteins by muscle in vitro and in vivo. Results Our results revealed a dramatic increased muscular production (2-to 25-fold) of several acute phase reactants (APR: haptoglobin, serpina3n, complement C3, serum amyloid A1) which are released in the circulation during C26 cancer cachexia. This observation was confirmed in two 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. Our results showed also that IL-6 plays a major role in the muscular induction of these APR in vivo, while glucocorticoids and pro-inflammatory cytokines stimulate directly their increased expression in muscle cells in vitro. Conclusions Muscle wasting caused by cancer is associated with marked changes in muscle secretome. 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.