Nascimento, C. M. | Search bioRxiv

bioRxiv2025

Pediatric CHOP Chemotherapy Acutely Disrupts Satellite-Cell Dynamics and Blunts Muscle Mass in a Sex-Specific Manner

Pediatric cancer survival now exceeds 85 percent owing, in part, advances and use of combination chemotherapy treatments such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone). Despite its efficacy, CHOP may cause deleterious 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 day 28 to 48. CHOP slowed body-weight gain and has smaller gastrocnemius fiber cross-sectional area by approximately 25 percent in both sexes. mRNA 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 a 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-cell depletion as a potential target for preserving muscle health in pediatric cancer survivors.

physiology↗

bioRxiv2025

Differential regulation of mitochondrial quality control in skeletal muscle by HZE radiation exposure and partial weightbearing in mice

Spaceflight places astronauts under both reduced mechanical loading and ionizing radiation, each of which can compromise skeletal muscle health. We investigated whether 21 days of simulated lunar gravity (one sixth G) with or without a single 0.5 Gy dose of 28Si heavy ion radiation alters transcriptional regulators of mitochondrial quality control in mouse gastrocnemius muscle. Female BALB/cByJ mice were assigned to four groups: Sham + 1 G (SHAM+CC), Rad + 1 G (RAD+CC), Sham + G/6 (SHAM+G/6), Rad + G/6 (RAD+G/6) and relative mRNA levels of key regulators of mitochondrial biogenesis, mitophagy, dynamics and electron transport chain content were measured by quantitative RT-PCR. Radiation significantly suppressed PGC-1 (p = 0.035) and TFAM (p = 0.051) transcripts and reduced LC3b (p = 0.033) and Park2 (p = 0.007) expression; no effects of simulated lunar gravity or interaction effects were detected. Composite scores confirmed suppression of biogenesis (p = 0.029) and a trend toward reduced mitophagy (p = 0.057). Transcripts encoding oxidative phosphorylation subunits and fusion and fission factors remained unchanged, suggesting preserved mitochondrial content and network homeostasis at day 21. These findings indicate that a single space relevant heavy ion exposure selectively disrupts early transcriptional steps of mitochondrial turnover without immediately altering organelle abundance of transcripts for electron transport chain or dynamics; in contrast simulated lunar gravity alone did not elicit changes in these pathways.

molecular biology↗