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

• Published in: Cell reports (Cambridge) Vol. 43; no. 8; p. 114587
• Main Authors: Zhang, Yichi, Dos Santos, Matthieu, Huang, Huocong, Chen, Kenian, Iyengar, Puneeth, Infante, Rodney, Polanco, Patricio M., Brekken, Rolf A., Cai, Chunyu, Caijgas, Ambar, Cano Hernandez, Karla, Xu, Lin, Bassel-Duby, Rhonda, Liu, Ning, Olson, Eric N.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 27.08.2024; Elsevier
• Subjects: AAV; atrophy; cachexia; CP: Cancer; CP: Metabolism; denervation; myogenin; myostatin; single nucleus ATAC-seq; single nucleus multiome; single nucleus RNA-seq; single nucleus RNA-seq; denervation; myogenin; CP: Metabolism; AAV; CP: Cancer; single nucleus multiome; cachexia; single nucleus ATAC-seq; atrophy; myostatin
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114587

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. [Display omitted] •KIC is a pancreatic cancer model manifesting severe cancer cachexia-induced muscle atrophy•Multi-omics analysis reveals activation of denervation-responsive and catabolic genes in KIC muscle•Inhibition of the myogenin-myostatin axis rescues muscle atrophy in KIC mice In this study, Zhang et al. show that denervation-responsive and catabolic genes are induced in cachexic muscle from a genetic mouse model of pancreatic cancer. The activation of a myogenin-myostatin axis drives muscle atrophy in this model, and muscle atrophy can be rescued by inhibiting myogenin or myostatin.