FOXO-regulated DEAF1 controls muscle regeneration through autophagy

Abstract

The commonality between various muscle diseases is the loss of muscle mass, function, and regeneration, which severely restricts mobility and impairs the quality of life. With muscle stem cells (MuSCs) playing a key role in facilitating muscle repair, targeting regulators of muscle regeneration has been shown to be a promising therapeutic approach to repair muscles. However, the underlying molecular mechanisms driving muscle regeneration are complex and poorly understood. Here, we identified a new regulator of muscle regeneration, Deaf1 (Deformed epidermal autoregulatory factor-1) - a transcriptional factor downstream of foxo signaling. We showed that <i>Deaf1</i> is transcriptionally repressed by FOXOs and that DEAF1 targets to <i>Pik3c3</i> and <i>Atg16l1</i> promoter regions and suppresses their expression. <i>Deaf1</i> depletion therefore induces macroautophagy/autophagy, which in turn blocks MuSC survival and differentiation. In contrast, <i>Deaf1</i> overexpression inactivates autophagy in MuSCs, leading to increased protein aggregation and cell death. The fact that <i>Deaf1</i> depletion and its overexpression both lead to defects in muscle regeneration highlights the importance of fine tuning DEAF1-regulated autophagy during muscle regeneration. We further showed that <i>Deaf1</i> expression is altered in aging and cachectic MuSCs. Manipulation of <i>Deaf1</i> expression can attenuate muscle atrophy and restore muscle regeneration in aged mice or mice with cachectic cancers. Together, our findings unveil an evolutionarily conserved role for DEAF1 in muscle regeneration, providing insights into the development of new therapeutic strategies against muscle atrophy.<b>Abbreviations</b>: DEAF1: Deformed epidermal autoregulatory factor-1; FOXO: Forkhead box O; MuSC: Muscle Stem Cell; PAX7: Paired box 7; PIK3C3: Phosphatidylinositol 3-kinase catalytic subunit type 3.