Long-chain acyl-CoA synthetase 6 (ACSL6)
mRNA is present in human and rat skeletal muscle, and is modulated by nutritional status: exercise and fasting decrease ACSL6
mRNA, whereas acute
lipid ingestion increase its expression. ACSL6 genic inhibition in rat primary myotubes decreased
lipid accumulation, as well as activated the higher mitochondrial oxidative capacity programme and
fatty acid oxidation through the AMPK/PGC1-α pathway. ACSL6 overexpression in human primary myotubes increased
phospholipid species and decreased oxidative metabolism.
ABSTRACT:
Long-chain acyl-CoA synthetases (ACSL 1 to 6) are key
enzymes regulating the partitioning of
acyl-CoA species toward different metabolic fates such as
lipid synthesis or β-oxidation. Despite our understanding of ecotopic
lipid accumulation in skeletal muscle being associated with
metabolic diseases such as
obesity and type II diabetes, the role of specific ACSL
isoforms in
lipid synthesis remains unclear. In the present study, we describe for the first time the presence of ACSL6
mRNA in human skeletal muscle and the role that ACSL6 plays in
lipid synthesis in both rodent and human skeletal muscle. ACSL6
mRNA was observed to be up-regulated by acute high-fat meal ingestion in both rodents and humans. In rats, we also demonstrated that fasting and chronic aerobic training negatively modulated the ACSL6
mRNA and other genes of
lipid synthesis. Similar results were obtained following ACSL6 knockdown in rat myotubes, which was associated with a decreased accumulation of TAGs and lipid droplets. Under the same knockdown condition, we further demonstrate an increase in
fatty acid content, p-AMPK, mitochondrial content, mitochondrial respiratory rates and
palmitate oxidation. These results were associated with increased PGC-1α, UCP2 and UCP3
mRNA and decreased
reactive oxygen species production. In human myotubes, ACSL6 overexpression reduced
palmitate oxidation and PGC-1α
mRNA. In conclusion, ACSL6 drives
acyl-CoA toward
lipid synthesis and its downregulation improves mitochondrial biogenesis, respiratory capacity and
lipid oxidation. These outcomes are associated with the activation of the AMPK/PGC1-α pathway.