ACSS2 involved in acetyl-CoA synthesis regulates skeletal muscle function

Acyl-coenzyme A synthetase short-chain family member-2 (ACSS2) catalyzes the conversion of acetate to acetyl-CoA, regulating cholesterol metabolism. Given the discovery of a muscular dystrophy associated with 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), a key enzyme in cholesterol synthesis, we studied Acss2 in mice and the orthologous gene AcCoA in flies. Skeletal muscle from Acss2^-/- mice showed atrophic fibers, lipid accumulation, and depleted NADH levels, while myoblasts from these mice displayed precocious differentiation. Exercise induced fatigue in the Acss2^-/- mice, which was accentuated by inhibition of ATP-citrate lyase (ACLY) activity. AcCoA knockdown yielded reduced body sizes and locomotor defects in Drosophila. ACSS2 is vital for skeletal muscle function and merits study as a potential factor in muscle diseases related to cholesterol metabolism. Impact statement ACSS2 catalyzes the conversion of acetate to acetyl-CoA, regulating cholesterol metabolism. Given the increasingly apparent links between cholesterol metabolism and skeletal muscle function, we investigated ACSS2 deficiency in mouse and fly models. We identified defects in muscle morphology, muscle metabolism, and motor function. ACSS2 is vital for skeletal muscle.