Examination of the role of autonomic innervation in muscle stem cell aging

About This Grant

PROJECT SUMMARY Sarcopenia, characterized by the loss of skeletal muscle mass and function with age, affects 10-22% of the global adult population and accounts for 1.5% of total formal healthcare costs in the United States. Sarcopenia significantly increases rates of mortality, hospitalization, cognitive impairment, falls, and depression, particularly among the elderly. With no approved pharmacological treatments, current interventions are limited to increased exercise and enhanced nutrition. However, clinical trials for these interventions have consistently failed to increase muscle mass despite improving muscle strength. Increases in muscle mass generally require the incorporation of new muscle nuclei derived from muscle stem cells (MuSCs). Since the discovery of muscle stem cells in 1961, many regulators of MuSC activity have been elucidated, but there has been limited success in identifying druggable targets for improving muscle healthspan. Recent discoveries in other stem cell systems, such as blood, intestine, and skin, have highlighted the key role of the autonomic nervous system (ANS) in regulating stem cell biology. While the autonomic innervation of skeletal muscle is well studied, we know little about the direct effects of the ANS on MuSCs. We propose to investigate the functional link between ANS neurons and MuSCs using a novel model in Drosophila melanogaster. We have developed methods to leverage the Drosophila genetic toolkit to image and manipulate both the ANS and MuSCs in adult flies and have obtained preliminary evidence showing a robust direct innervation of MuSCs by the axons of autonomic neurons in adult fly muscles. We also find that this innervation degrades with age. Our proposal will refine whole-body imaging methods and genetic tools for robust and faithful labeling of the ANS and MuSCs. We will investigate changes in the counts and spatial distribution of MuSCs and innervating autonomic neurons across the lifespan and during the course of regeneration from injury. We will identify the signaling molecules mediating the regulation of MuSCs by the ANS and adapt existing tools for the suppression or enhancement of neurotransmitter release in the ANS or their receptors in MuSCs. Lastly, we will modify existing protocols for isolating MuSCs form dissected muscle preparations to allow the extraction and sequencing of transcripts from single MuSCs to survey gene expression changes downstream of ANS modulation in both aging and injury repair contexts. By genetically dissecting the relationship between ANS and MuSCs, our proposed work will identify new molecular regulators of muscle aging, paving the way for alternative therapeutic approaches aimed at treatment of MuSC decline with age and improving muscle health.