A molecular pathway for cancer cachexia-induced muscle atrophy revealed at single-nucleus resolution
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.
Authors
- Chunyu Cai (ORCID: https://orcid.org/0000-0001-8808-4779)
- Kenian Chen (ORCID: https://orcid.org/0000-0002-4083-841X)
- Rhonda Bassel‐Duby (ORCID: https://orcid.org/0000-0001-7568-410X)
- Puneeth Iyengar (ORCID: https://orcid.org/0000-0003-3740-7915)
- Patricio Marcelo Polanco (ORCID: https://orcid.org/0000-0002-1719-1208)
- Rodney E. Infante (ORCID: https://orcid.org/0000-0003-2605-822X)
- Matthieu Dos Santos (ORCID: https://orcid.org/0000-0002-7113-102X)
- Huocong Huang (ORCID: https://orcid.org/0000-0002-6345-4566)
- Karla Cano Hernandez (ORCID: https://orcid.org/0000-0002-6810-141X)
- Eric N. Olson (ORCID: https://orcid.org/0000-0003-1151-8262)
- Rolf A. Brekken (ORCID: https://orcid.org/0000-0003-2704-2377)
- Yichi Zhang (ORCID: https://orcid.org/0000-0002-2280-7599)
- Ning Liu (ORCID: https://orcid.org/0000-0002-8517-0652)
- Lin Xu (ORCID: https://orcid.org/0000-0001-6490-1471)
- Ambar Caijgas
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- Southwestern Medical Center (US)
- Southwestern Medical Center (US)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2024-08-01
- DOI
- https://doi.org/10.1016/j.celrep.2024.114587
- Citations
- 18
- Primary Topic
- Muscle Physiology and Disorders
- Type
- article
- Field-Weighted Citation Impact
- 4.21
Funders
- Cancer Prevention and Research Institute of Texas
- National Institutes of Health