ACSS2 involved in acetyl-CoA synthesis regulates skeletal muscle function

Area of Science:

• Biochemistry
• Molecular Biology
• Genetics

Background:

• Acyl-coenzyme A synthetase short-chain family member-2 (ACSS2) converts acetate to acetyl-CoA, impacting cholesterol metabolism.
• Cholesterol metabolism is increasingly linked to skeletal muscle function and disease.
• Muscular dystrophy has been associated with HMGCR, a key enzyme in cholesterol synthesis.

Purpose of the Study:

• To investigate the role of ACSS2 in skeletal muscle function.
• To explore the consequences of ACSS2 deficiency in mouse and fly models.

Main Methods:

• Studied Acss2 knockout mice (Acss2^-/-) and AcCoA knockdown in Drosophila.
• Analyzed skeletal muscle morphology, lipid accumulation, NADH levels, and myoblast differentiation in mice.
• Assessed exercise-induced fatigue in mice, including effects of ATP-citrate lyase (ACLY) inhibition.
• Evaluated body size and locomotor activity in Drosophila.

Main Results:

• Acss2^-/- mice exhibited skeletal muscle atrophy, lipid accumulation, and reduced NADH levels.
• Myoblasts from Acss2^-/- mice showed precocious differentiation.
• Acss2^-/- mice experienced exercise-induced fatigue, worsened by ACLY inhibition.
• AcCoA knockdown in flies resulted in reduced body size and locomotor defects.

Conclusions:

• ACSS2 is vital for maintaining skeletal muscle morphology, metabolism, and function.
• ACSS2 deficiency leads to significant muscle defects and motor impairments.
• ACSS2 warrants further investigation as a potential factor in muscle diseases linked to cholesterol metabolism.