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 E. Infante, Patricio M. Polanco, Rolf A. Brekken, Chunyu Cai, Ambar Caijgas, Karla Cano Hernandez, Lin Xu, Rhonda Bassel‐Duby, Ning Liu, Eric N. Olson
Abstract
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.