ATAD2 is a novel regulator of myogenesis and autophagy in skeletal muscles

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Abstract The nuclear protein ATAD2 (ATPase family AAA domain containing 2) is a known positive regulator of cell proliferation in various cancer types. The expression and functional roles of ATAD2 in skeletal muscle cells are unknown. In this study, we used transient and stable knockdown approaches using siRNA and shRNA oligos to evaluate how ATAD2 regulates proliferation, migration, differentiation, and autophagy in C2C12 myoblasts. Atad2 knockdown (KD) significantly increased myoblast proliferation rate, S-phase entry, overall cell viability, and early differentiation into myotubes. However, Atad2 KD also elicited myotube atrophy and upregulation of ubiquitin E3 ligases Atrogin-1 and MuRF1. Basal autophagy was inhibited in Atad2 KD cells as a result of downregulation of autophagy-related genes ( Lc3b , Gabarapl1 , Atg5 , and Atg7 ). Immunoblotting and immunostaining revealed significant decrease in LC3B protein levels and the number of LC3B punctae per cell with Atad2 KD, respectively. LAMP1 staining confirmed the presence of enlarged lysosomes in Atad2 KD cells. Additionally, genes involved in lysosome function and integrity including Rab7 , Rab29 , Rab32 , Nrbf2 , and Cathepsin L were downregulated in Atad2 KD cells. Collectively, these results indicate that ATAD2 is a critical regulator of muscle cell proliferation, differentiation, autophagy and lysosomal integrity.

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