Explore the vast range of titles available.

Background Tumour‐induced skeletal muscle wasting in the context of cancer cachexia is a condition with profound implications for patient survival. The loss of muscle mass is a significant clinical obstacle and is linked to reduced tolerance to chemotherapy and increased frailty. Understanding the molecular mechanisms driving muscle atrophy is crucial for the design of new therapeutics. Methods Lewis lung carcinoma tumours were utilized to induce cachexia and muscle atrophy in mice. Single‐nucleus libraries of the tibialis anterior (TA) muscle from tumour‐bearing mice and their non‐tumour‐bearing controls were constructed using 10X Genomics applications following the manufacturer's guidelines. RNA sequencing results were analysed with Cell Ranger software and the Seurat R package. Oxygen consumption of mitochondria isolated from TA muscle was measured using an Oroboros O2k‐FluoRespirometer. Mouse primary myotubes were treated with a recombinant ectodysplasin A2 (EDA‐A2) protein to activate EDA‐A2 receptor (EDA2R) signalling and study changes in gene expression and oxygen consumption. Results Tumour‐bearing mice were sacrificed while exhibiting moderate cachexia. Average TA muscle weight was reduced by 11% (P = 0.0207) in these mice. A total of 12 335 nuclei, comprising 6422 nuclei from the control group and 5892 nuclei from atrophying muscles, were studied. The analysis of single‐nucleus transcriptomes identified distinct myonuclear gene signatures and a shift towards type IIb myonuclei. Muscle atrophy‐related genes, including Atrogin1, MuRF1 and Eda2r, were upregulated in these myonuclei, emphasizing their crucial roles in muscle wasting. Gene set enrichment analysis demonstrated that EDA2R activation and tumour inoculation led to similar expression patterns in muscle cells, including the stimulation of nuclear factor‐kappa B, Janus kinase–signal transducer and activator of transcription and transforming growth factor‐beta pathways and the suppression of myogenesis and oxidative phosphorylation. Muscle oxidative metabolism was suppressed by both tumours and EDA2R activation. Conclusions This study identified tumour‐induced transcriptional changes in muscle tissue at single‐nucleus resolution and highlighted the negative impact of tumours on oxidative metabolism. These findings contribute to a deeper understanding of the molecular mechanisms underlying muscle wasting.

Background Lung cancer is the primary cause of cancer deaths worldwide. Activation of epidermal growth factor receptor (EGFR) leads to lung cancer progression and poor prognosis while involuntary weight loss remains a major problem. Tumour‐derived parathyroid hormone‐related protein (PTHrP) emerged as a potential mediator of cachexia. Here, we investigated the modulatory role of EGFR signalling in PTHrP (encoded by Pthlh) gene expression and the impact of this relationship on cancer cachexia. Methods Global gene expression profiles of Lewis lung carcinoma (LLC) cells were analysed. Pthlh mRNA levels were measured by qRT‐PCR in LLC cells treated with EGFR ligands and tyrosine kinase inhibitors (TKIs). LLC tumour‐bearing mice received EGFR TKI erlotinib for 7 days via intraperitoneal injection or oral gavage. Tumour Pthlh mRNA, weight of fat/muscle tissue, and grip strength were assessed. RNA‐seq data from The Cancer Genome Atlas and gene expression analysis tools were used to characterize expression profiles of PTHLH and EGFR along with correlation analysis of PTHLH with EGFR and transforming growth factor alpha (TGFA) in human lung cancer and head and neck squamous carcinoma (HNSC). Survival of lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) patients with EGFR gene alterations was analysed in regard to PTHLH expression. Results Expression of EGFR ligands, EGFR itself, and PTHrP co‐clusters in LLC cells. Activation of EGFR signalling with its ligands significantly increases (3.8‐fold, P < 0.0005) while EGFR TKIs significantly decrease (90%, P < 0.0005) Pthlh mRNA levels in LLC cells. Pthlh mRNA drops 65–75% (P < 0.0005) in tumours upon treatment of LLC tumour‐bearing mice with erlotinib while their muscle mass and grip strength increase (9.2% P < 0.05, 23% P < 0.005, respectively) compared with tumour‐bearing control mice. PTHLH is overexpressed in tumours of LUSC (45.8‐fold, P < 0.05) and HNSC (17.5‐fold, P < 0.05) compared with normal tissue. PTHLH expression correlates with EGFR and its ligand TGFA in both cancers (LUSC: n = 745, R = 0.32, P < 0.0001 and R = 0.51, P < 0.0001; HNSC: n = 545, R = 0.34, P < 0.001 and R = 0.50, P < 0.001, respectively). High PTHLH mRNA associates with poor overall survival in LUAD patients with activating EGFR mutations (n = 40, log‐rank test, P = 0.0451). Conclusions Epidermal growth factor receptor signalling regulates expression of cachexia mediator PTHrP. EGFR inhibition reduces PTHrP expression in LLC tumours and ameliorates cachexia in LLC tumour‐bearing mice.

Skeletal muscle atrophy is a hallmark of the cachexia syndrome that is associated with poor survival and reduced quality of life in patients with cancer 1 . Muscle atrophy involves excessive protein catabolism and loss of muscle mass and strength 2 . An effective therapy against muscle wasting is currently lacking because mechanisms driving the atrophy process remain incompletely understood. Our gene expression analysis in muscle tissues indicated upregulation of ectodysplasin A2 receptor (EDA2R) in tumour-bearing mice and patients with cachectic cancer. Here we show that activation of EDA2R signalling promotes skeletal muscle atrophy. Stimulation of primary myotubes with the EDA2R ligand EDA-A2 triggered pronounced cellular atrophy by induction of the expression of muscle atrophy-related genes Atrogin1 and MuRF1 . EDA-A2-driven myotube atrophy involved activation of the non-canonical NFĸB pathway and was dependent on NFκB-inducing kinase (NIK) activity. Whereas EDA-A2 overexpression promoted muscle wasting in mice, deletion of either EDA2R or muscle NIK protected tumour-bearing mice from loss of muscle mass and function. Tumour-induced oncostatin M (OSM) upregulated muscle EDA2R expression, and muscle-specific oncostatin M receptor (OSMR)-knockout mice were resistant to tumour-induced muscle wasting. Our results demonstrate that EDA2R–NIK signalling mediates cancer-associated muscle atrophy in an OSM–OSMR-dependent manner. Thus, therapeutic targeting of these pathways may be beneficial in prevention of muscle loss. Gene expression analysis in muscle tissues showed upregulation of ectodysplasin A2 receptor in tumour-bearing mice and patients with cachectic cancer, and thus therapeutic targeting of relevant pathways may be beneficial in prevention of muscle loss.

Tumor-induced skeletal muscle wasting in the context of cancer cachexia is a condition with profound implications for patient survival. The loss of muscle mass is a significant clinical obstacle and is linked to reduced tolerance to chemotherapy and increased frailty. We investigated muscle gene expression at single nucleus level in cachectic mice and revealed distinct myonuclear gene signatures and a shift towards type IIb myonuclei. Notably, atrophy-related genes, including Atrogin1, MuRF1 and Eda2r were upregulated in these myonuclei, emphasizing their crucial role in muscle wasting. Activation of the Ectodysplasin A2 Receptor (EDA2R) pathway suppressed gene sets related to muscle contraction and oxidative metabolism, indicating its involvement in transcriptional reprogramming. Our study also highlighted the negative impact of tumors on oxidative metabolism in muscle tissue and their influence on the transcriptomes of mononuclear cells in skeletal muscle. These findings contribute to a deeper understanding of the molecular mechanisms underlying cancer cachexia.

Progressive weakness and muscle loss are associated with multiple chronic conditions including muscular dystrophy and cancer. Cancer-associated cachexia, characterized by dramatic weight loss and fatigue, leads to reduced quality of life and poor survival. Inflammatory cytokines have been implicated in muscle atrophy, however, available anti-cytokine therapies failed to prevent muscle wasting in cancer patients. We previously reported that muscle-specific deletion of the Oncostatin M (OSM) receptor (OSMR) preserved muscle mass and function in tumor-bearing mice. Here, we show that OSM is a potent inducer of muscle atrophy. OSM triggers cellular atrophy in primary myotubes utilizing the JAK/STAT3 pathway. Identification of OSM targets by RNA sequencing revealed the induction of various muscle atrophy-related genes, including Atrogin1. OSM overexpression in mice caused muscle wasting while the neutralization of circulating OSM protected from tumor-driven loss of muscle mass and function. Our results indicate that activated OSM/OSMR signaling drives muscle atrophy, and the therapeutic targeting of this pathway may be useful in preventing muscle wasting.Competing Interest StatementThe authors have declared no competing interest.Footnotes* https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE222208

Skeletal muscle atrophy is a hallmark of the cachexia syndrome that is associated with poor survival and reduced quality of life in cancer patients. Muscle atrophy involves excessive protein catabolism and loss of muscle mass and strength. An effective therapy against muscle wasting is lacking as mechanisms driving the atrophy process remain incompletely understood. Our gene expression analysis in muscle tissues revealed upregulation of Ectodysplasin A2 Receptor (EDA2R) in tumor-bearing mice and cachectic cancer patients. Here we show that activation of EDA2R signaling promotes skeletal muscle atrophy. Stimulation of primary myotubes with EDA2R ligand, EDA-A2, triggered pronounced cellular atrophy via inducing the expression of muscle atrophy-related genes Atrogin1 and MuRF1. EDA-A2-driven myotube atrophy involved activation of the noncanonical NFĸB pathway and depended on NIK kinase activity. While EDA-A2 overexpression induced muscle wasting in mice, the deletion of EDA2R or muscle NIK protected tumor-bearing mice from the loss of muscle mass and function. Tumor-induced Oncostatin M upregulated muscle EDA2R expression and muscle-specific Oncostatin M Receptor (OSMR) knockout mice were resistant to tumor-driven muscle wasting. Our results demonstrate that EDA2R/NIK signaling mediates cancer-associated muscle atrophy in an OSM/OSMR-dependent manner. Thus, therapeutic targeting of these pathways may be beneficial in preventing muscle loss.Competing Interest StatementThe authors have declared no competing interest.