Cell Reports (Aug 2024)

A molecular pathway for cancer cachexia-induced muscle atrophy revealed at single-nucleus resolution

  • Yichi Zhang,
  • Matthieu Dos Santos,
  • Huocong Huang,
  • Kenian Chen,
  • Puneeth Iyengar,
  • Rodney Infante,
  • Patricio M. Polanco,
  • Rolf A. Brekken,
  • Chunyu Cai,
  • Ambar Caijgas,
  • Karla Cano Hernandez,
  • Lin Xu,
  • Rhonda Bassel-Duby,
  • Ning Liu,
  • Eric N. Olson

Journal volume & issue
Vol. 43, no. 8
p. 114587

Abstract

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Summary: Cancer cachexia is a prevalent and often fatal wasting condition that cannot be fully reversed with nutritional interventions. Muscle atrophy is a central component of the syndrome, but the mechanisms whereby cancer leads to skeletal muscle atrophy are not well understood. We performed single-nucleus multi-omics on skeletal muscles from a mouse model of cancer cachexia and profiled the molecular changes in cachexic muscle. Our results revealed the activation of a denervation-dependent gene program that upregulates the transcription factor myogenin. Further studies showed that a myogenin-myostatin pathway promotes muscle atrophy in response to cancer cachexia. Short hairpin RNA inhibition of myogenin or inhibition of myostatin through overexpression of its endogenous inhibitor follistatin prevented cancer cachexia-induced muscle atrophy in mice. Our findings uncover a molecular basis of muscle atrophy associated with cancer cachexia and highlight potential therapeutic targets for this disorder.

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