Satellite cells protect against pediatric chemotherapy-induced delays in muscle growth and development

About This Grant

PROJECT SUMMARY. Pediatric cancer affects thousands of children each year, and while advancements in treatment have markedly improved survival rates, the adverse effects of chemotherapy on skeletal muscle growth and function remain a significant and understudied clinical concern. The standard chemotherapy regimen used to treat many types of pediatric cancers, such as leukemia, lymphoma, and brain cancers, consists of cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), vincristine sulfate (Oncovin), and prednisone (CHOP). Although this regimen is effective at killing cancer cells, CHOP leads to blunted muscle growth and compromised motor development, in addition to impairing muscle stem cell (i.e., satellite cell) function. Given the essential role of satellite cells in muscle growth during early development, interventions aimed at preserving their activity may mitigate these harmful effects. The proposed research hypothesizes that pharmacologic activation of satellite cells will prevent CHOP-induced defects on muscle growth and development in pediatric mice. Specific Aim 1 will assess whether enhancing satellite cell proliferation using a small molecule (CEP-701) or transient overexpression of MYC specifically in satellite cells (Pax7-MYC) can protect muscle growth and development during CHOP treatment. This aim will be completed using a myonuclear labeling model, microCT assessment of body composition, skeletal muscle histology and single muscle fiber quantification of myonuclei, and single nuclear and cell RNA sequencing. Specific Aim 2 will define the impact of CHOP on myonuclear gene transcription and chromatin accessibility in newly fused satellite cells through the use our myonuclear-labeling (HSA-GFP) mouse model, in addition to spatial and single cell RNA sequencing. This approach will allow us to identify and quantify resident and newly fused (satellite cell-derived) myonuclei to determine if the CHOP-mediated alterations in the satellite cell transcriptome is carried over to the muscle fiber upon satellite cell fusion. Specific Aim 3 quantifies the longitudinal impact of CHOP on skeletal muscle mass, physical function, glucose metabolism and insulin sensitivity, and rate of age-mediated muscle atrophy. Upon successful completion of Aim 3, we will have a more complete picture regarding the impact of pediatric chemotherapy on skeletal muscle homeostasis and aging. The project’s innovative approach will provide the first in vivo assessment of satellite cell-targeted therapies for chemotherapy-induced muscle damage in pediatric models and will demonstrate the enduring consequences of childhood chemotherapy on muscle development through the fusion of defective satellite cells. This study will have a significant impact by informing therapeutic strategies to preserve musculoskeletal health in childhood cancer survivors and by identifying new molecular targets to prevent or reverse long-term muscle dysfunction.