Impaired Barrier Integrity of the Skeletal Muscle Vascular Endothelium Drives Progression of Cancer Cachexia

Abstract

Cancer patients experience cachexia, which is characterized by extensive skeletal muscle wasting that worsens the quality of life and increases mortality. Currently, there are no approved treatments that can effectively counteract cancer cachexia. Vascular endothelial cells (ECs) are essential for maintaining tissue perfusion, nutrient supply, and preventing inappropriate transmigration of immune cells into the tissue. However, little is known about the role of the muscle vasculature in cancer cachexia. We hypothesized that endothelial dysfunction in the skeletal muscle mediates cancer cachexia. Using transgenic pancreatic ductal adenocarcinoma (PDAC) mice and a tissue clearing and high-resolution 3D-tissue imaging approach, we found that the loss of skeletal muscle vascular density precedes the loss of muscle mass. Importantly, we show that cancer cachexia patients exhibit significantly decreased muscle vascular density and severe muscle atrophy when compared to non-cancer patients. Unbiased single cell transcriptomic analyses of the muscle endothelium unveiled a unique EC population present in cachexia muscles. Increased circulating Activin-A suppresses the expression of the transcriptional co-activator PGC1alpha in the muscle endothelium, thus disrupting junctional integrity in the vasculature and increasing vascular leakage. Conversely, restoration of endothelial-specific PGC1alpha prevented the decreased vascular density and muscle loss observed in tumor-bearing mice. Our study suggests that EC-PGC1alpha is essential for maintaining the integrity of the skeletal muscle vascular barrier and that restoring muscle endothelial function could be a valuable therapeutic approach to prevent or reverse cancer cachexia.

Tumor-induced alterations in single-nucleus transcriptome of atrophying muscles indicate enhanced protein degradation and reduced oxidative metabolism

“…In fact, a recent study utilizing cachexia-inducing tumor models described weakened vascular functions in atrophying muscles. 37 In skeletal muscle tissue, tumors likely exert an extensive impact that does not merely target myofibers. Finally, gene sets identified in this study contribute significantly to our understanding of potential therapeutic targets for mitigating cancer cachexia and associated muscle wasting.…”

Cardiac atrophy, dysfunction, and metabolic impairments: a cancer-induced heart failure phenotype

“…24 Recently, the loss of vascular density was observed in skeletal muscle of tumor-bearing mice, which preceded the decline in muscle function and mass. 25 Thus, endothelial cells that line the vessels of distant, non-metastatic organs are ideally situated as first responders to factors extruded from the primary tumor. We are the first to show that malignancy causes a loss of capillary density in the myocardium.…”

A high-resolution view of the heterogeneous aging endothelium

“…EC dysfunction has been repeatedly shown to be associated with increased phenotypes of frailty and sarcopenia [ 61 ]. Moreover, recent findings indicate that skeletal muscle vascular attrition precedes cachexia in a mouse model of pancreatic ductal adenocarcinoma, and is associated with increased vascular leakiness and immune cell infiltration [ 62 ]. In line with muscle EC phenotypes in healthy aging, scRNA-seq revealed that muscles in cachexic mice harbor a unique EC subtype with a gene expression signature indicative of decreased angiogenesis and increased immunoregulation.…”

“…In line with muscle EC phenotypes in healthy aging, scRNA-seq revealed that muscles in cachexic mice harbor a unique EC subtype with a gene expression signature indicative of decreased angiogenesis and increased immunoregulation. Additionally, multiple cofactors of the transcriptional coactivator PGC1α were found expressed in this EC subtype, which were functionally validated to be important for maintenance of muscle vascular barrier integrity [ 62 ].…”