Details

Autor(en) / Beteiligte

• 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.

Titel

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

Ist Teil von

• Cell reports (Cambridge), 2024-08, Vol.43 (8), p.114587-114587, Article 114587

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2024

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.