Mitochondrial biogenesis and transfer to promote muscle regeneration

Fibroadipoprogenitors (FAPs) are muscle stem cells that play a central role in maintaining muscle homeostasis. In systemic chronic illnesses as well as musculoskeletal injuries, FAPs mediate muscle degeneration through differentiation into fibrotic and fatty tissue, leading to declining muscle function which is associated with decreased quality of life and shortened lifespan. While the role of FAPs in muscle degeneration has been increasingly characterized in the last decade, we have found that certain stimuli including B-agonism and intermittent ischemia/reperfusion (pre-conditioning) can induce a beige fat phenotype that promotes muscle regeneration in vitro as well as in vivo. We have shown that beige-FAPs are capable of mitochondrial transfer which is thought to be a mechanism by which other stem cells are able to rescue injured cells to promote regeneration. The objective of this project is to define the role of mitochondrial function and transfer on the ability of FAPs to improve muscle regeneration. To determine this, begin by defining the mechanisms by which B-agonism can stimulate FAP mitochondrial transfer. We hypothesize that B-agonism will stimulate FAPs to a beige phenotype that will promote mitochondrial biogenesis and the formation of tunneling nanotube machinery. We will next determine the intrinsic properties of FAP mitochondria and impact of FAP-mitochondrial donation on myogenic cell proliferation, differentiation, and myogenic commitment We hypothesize that beige- FAPs contain both enhanced mitochondrial numbers, but also increased bioenergetics that promote muscle stem cell proliferation and differentiation. Finally, we will evaluate how B-agonist treatment or pre-conditioning can stimulate beige-FAPs mitochondrial transfer in vivo to improve outcomes in the setting of ischemia-reperfusion injury. The proposed work is important as it will define the mechanism by which beige-FAPs can promote muscle regeneration. An increased understanding of this mechanism in vitro and in vivo may assist in the rational design of treatment strategies to improve muscle degeneration.