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

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-induced gene program that upregulates the transcription factor myogenin. Further studies showed that a myogenin-myostatin pathway promotes muscle atrophy in response to cancer cachexia. shRNA 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 cancer cachexia-induced muscle atrophy and highlight potential therapeutic targets for this disorder. Overall design: Comparative gene expression profiling analysis of single nucleus RNA-seq data for three biological replicates of Gastrocnemius-plantaris (GP) muscles from control and a mouse model with cancer cachexia (KIC) at 66 days of age.