Pediatric CHOP chemotherapy acutely disrupts satellite-cell dynamics and blunts muscle mass in a sex-specific manner

Pediatric cancer survival now exceeds 85% owing, in part, to advances and the use of combination chemotherapy treatments such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone). Despite its efficacy, CHOP may cause off-target effects during critical pediatric development periods such as impairments of skeletal muscle. We evaluated the acute effects of a CHOP administered to C57Bl/6J mice from postnatal <i>day 28</i> to <i>48</i>. CHOP slowed body-weight gain and led to a smaller gastrocnemius fiber cross-sectional area by ∼25% in both sexes (<i>n</i> = 11 or 12 males; <i>n</i> = 8 or 9 females). RNA sequencing detected 214 differentially expressed genes in males and 217 in females relative to controls, yet only 29 transcripts overlapped. Males exhibited downregulation of myogenic regulators, indicating impaired progenitor maintenance, whereas females showed an upregulation of extracellular-matrix and translational machinery genes plus cell-cycle regulators. Using immunohistochemistry to assess satellite cell abundance, there were 60% fewer satellite cells in males and 40% fewer in females, which supported our transcriptional findings. These results demonstrate that pediatric CHOP acutely disrupts muscle stem-cell dynamics via sex-specific molecular programs and identify satellite cells as a potential target for preserving muscle health in pediatric cancer survivors.<b>NEW & NOTEWORTHY</b> Multiagent CHOP chemotherapy in juvenile mice impairs muscle growth and alters transcriptional programs in a sex-specific manner. CHOP-treated mice showed lower satellite cell abundance and smaller muscle fibers, with RNA-seq revealing distinct gene expression profiles enriched for myogenic regulators, extracellular matrix, and translational machinery. These findings highlight the negative effects of chemotherapy on developing muscle and suggest alterations to satellite cells as a key contributor.