Understanding regulation of pediatric regenerative myogenesis and its implication for muscle disease

ABSTRACT The maintenance of healthy skeletal muscle and its regeneration following acute injury involves precise regulation of the resident stem cell response by the surrounding muscle niche. Pediatric muscles respond quickly and are more proficient at regenerating from injury. The decline in regenerative capacity of geriatric muscle is widely studied, where the muscle niche is recognized to be a key contributor in the decline of the regenerative capacity of the muscle stem cells. However, the factors that support efficient regenerative capacity of pediatric muscle are less understood. The limited work in this area has focused on ex vivo examination of the intrinsic myogenic capacity of muscle stem cells but fails to capture the role of the muscle niche in driving pediatric muscle regeneration. An understanding of this is required as multiple degenerative muscle diseases, such as DMD, manifest from early childhood, where therapies that can maintain or further enhance pediatric muscle regenerative capacity can ameliorate the impact of this disease. The work proposed here aims to address this knowledge gap by building on our preliminary studies implicating the interplay of immune and stromal factors in the muscle niche for efficient regenerative myogenesis of pediatric muscle (Aim 1) and identify how these interactions are impaired in dystrophic that attenuates regenerative myogenesis and how targeting this holds therapeutic potential (Aim 2). We will make use of a combination of single-cell and spatial RNA transcriptomic analyses together with various DMD mouse models and patient samples to examine this process and validate our findings. Through use of these complimentary approaches the work here will provide basic insights into the regulation of healthy pediatric regenerative myogenesis with broad applicability to DMD and other pediatric onset degenerative muscle wasting diseases.