biostudies-literatureZhang YNICHD NIH HHSNHLBI NIH HHSNCI NIH HHSNIAMS NIH HHS114587https://www.ebi.ac.uk/biostudies/studies/S-EPMC11472345biostudies-literatureUnknown43(8)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 pCell reportsA molecular pathway for cancer cachexia-induced muscle atrophy revealed at single-nucleus resolution.PMC11472345R01 AR067294P50 HD087351R01 AR071980P30 CA008748R01 HL130253U54 HD087351P30 CA142543R01 AR080676Xu LPolanco PMBrekken RAChen KLiu NHuang HBassel-Duby RDos Santos MCai CZhang YCano Hernandez KIyengar PInfante ROlson ENCaijgas AfalseA 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 p2024-01-01T00:00:00Z2024 Aug2025-04-04T01:25:36.009Z2025-04-04T01:25:36.009ZS-EPMC114723453911620810.1016/j.celrep.2024.114587