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<p>Cachexia is the wasting of skeletal muscle in cancer and is a major complication that impacts a person’s quality of life. We hypothesized that cachexia is mediated by dysfunction of the vascular system, which is essential for maintaining perfusion and tempering inappropriate immune responses. Using transparent tissue topography, we discovered that loss of muscle vascular density precedes muscle wasting in multiple complementary tumor models, including pancreatic adenocarcinoma, colon carcinoma, lung adenocarcinoma and melanoma models. We also observed that persons suffering from cancer cachexia exhibit substantial loss of muscle vascular density. As tumors progress, increased circulating activin A remotely suppresses the expression of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α) in the muscle endothelium, thus inducing vascular leakage. Restoring endothelial PGC1α activity preserved vascular density and muscle mass in tumor-bearing mice. Our study suggests that restoring muscle endothelial function could be a valuable therapeutic approach for cancer cachexia.</p>

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Skeletal muscle endothelial dysfunction through the activin A–PGC1α axis drives progression of cancer cachexia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月26日

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  • Young-Mee Kim,
  • Mark A. Sanborn,
  • Shaluah Vijeth,
  • Priyanka Gajwani,
  • Xinge Wang,
  • Dahee Jung,
  • Tibor Valyi-Nagy,
  • Sreeparna Chakraborty,
  • Georgina Mancinelli,
  • Peter T. Toth,
  • Evan H. Phillips,
  • Paul Grippo,
  • Ameen A. Salahudeen,
  • Jooman Park,
  • Su Yeon Yeon,
  • Vijayalakshmi Ananthanarayanan,
  • Yuwei Jiang,
  • Steve Seung-Young Lee,
  • Klara Valyi-Nagy,
  • Jalees Rehman

摘要

Cachexia is the wasting of skeletal muscle in cancer and is a major complication that impacts a person’s quality of life. We hypothesized that cachexia is mediated by dysfunction of the vascular system, which is essential for maintaining perfusion and tempering inappropriate immune responses. Using transparent tissue topography, we discovered that loss of muscle vascular density precedes muscle wasting in multiple complementary tumor models, including pancreatic adenocarcinoma, colon carcinoma, lung adenocarcinoma and melanoma models. We also observed that persons suffering from cancer cachexia exhibit substantial loss of muscle vascular density. As tumors progress, increased circulating activin A remotely suppresses the expression of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α) in the muscle endothelium, thus inducing vascular leakage. Restoring endothelial PGC1α activity preserved vascular density and muscle mass in tumor-bearing mice. Our study suggests that restoring muscle endothelial function could be a valuable therapeutic approach for cancer cachexia.