Abstract
Background:
Preterm birth-related conditions affect the development of multiple organs, such as the heart, the lungs and the brain, leading to long-term alterations in their function and a higher risk of comorbidities. Emerging evidence also indicates that the skeletal muscles are affected. We aimed to understand the mechanisms underlying these changes in skeletal muscles.
Methods:
A rodent model of transient neonatal hyperoxia and muscle samples of human babies born at term or preterm were used to investigate the impact of preterm birth-related conditions on muscle stem cells, the engine of muscle growth and repair. Single cell transcriptomics, in vitro culture of myoblasts or single myofibres, ex vivo muscle contractile properties and in vivo experiments (cardiotoxin-induced muscle injury) were performed to determine the impact of preterm birth on muscle stem cell function and regenerative capacity.
Results:
Preterm birth-related conditions reduced the muscle stem cell pool from the newborn stage (-30%, p = 0.0134) until adulthood (-56%, p < 0.0001), along with impaired myogenic capacity and regenerative potential. In vitro analysis from rats showed impaired self-renewal and reduced myotube size (-28.8%, p = 0.004). Human samples suggest a similar trend towards smaller myotube size in muscle stem cells from infants born at the earlier gestational age. Single-cell RNA-seq on rat samples revealed an enriched TNF-α/NF-κB signalling pathway within subsets of muscle stem cells. This pathway, mediated in part by interaction with macrophages, influences muscle stem cell fate decisions and myogenic trajectories. Culture experiments showed that myotubes treated with conditioned medium from macrophages of rats exposed to hyperoxia have reduced diameters (-66.5%, p = 0.0216). Early administration of an inhibitor of TNF-α (Infliximab) restored the muscle stem cell pool postinjury (63%, p = 0.0073) and regenerative capacity.
Conclusions:
Overall, preterm birth-related conditions promote an inflammatory microenvironment that disrupts the muscle stem cell pool and their function. This mechanism could explain the muscle atrophy and weakness observed in individuals born preterm and suggests potential therapeutic strategies to improve overall health outcomes in this population.