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
Affiliations
Yichi Zhang
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Matthieu Dos Santos
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Huocong Huang
Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Kenian Chen
Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Puneeth Iyengar
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Rodney Infante
Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Patricio M. Polanco
Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Rolf A. Brekken
Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Chunyu Cai
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Ambar Caijgas
Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390, USA
Karla Cano Hernandez
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Lin Xu
Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Rhonda Bassel-Duby
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Ning Liu
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Corresponding author
Eric N. Olson
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Corresponding author
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.
