Translational Metabolism Research Laboratory

INTRODUCTION: Long-chain acyl-CoA synthetases (ACSLs) are implicated as regulators of oxidation and storage of fatty acids within skeletal muscle; however, to what extent diet and exercise alter skeletal muscle ACSLs remains poorly understood.

PURPOSE: To determine effects of diet and exercise training on skeletal muscle ACSLs and examine relationships between ACSL1 and ACSL6 and fat oxidation and fat storage, respectively.

METHODS: Male C57BL/6J mice consumed a 60% high-fat diet (HFD) for 12 weeks to induce obesity compared with low-fat diet (LFD). At week 4, mice began aerobic exercise (EX-Tr) or remained sedentary (SED) for 8 weeks. At week 12, protein abundance of 5 known ACSL isoforms and mRNA expression for ACSL1 and ACSL6 were measured in gastrocnemius muscle, as was skeletal muscle lipid content. Fat oxidation was measured using metabolic cage indirect calorimetry at week 10.

RESULTS: Of 5 known ACSL isoforms, 4 were detected at the protein level. HFD resulted in greater, yet non-significant, ACSL1 protein abundance (+18%, P=0.13 vs. LFD), greater ACSL6 (+107%, P<0.01 vs. LFD), and no difference in ACSL4 or ACSL5. Exercise training resulted in greater ACSL6 protein abundance in LFD mice (P=0.05 LFD EX-Tr vs. SED) while ACSL4 was lower following exercise training compared with sedentary, regardless of diet. Under fasted conditions, skeletal muscle ACSL1 protein abundance was not related to measures of whole-body fat oxidation. Conversely, skeletal muscle ACSL6 protein abundance was positively correlated with intramyocellular lipid content (P<0.01, r=0.22).We present evidence that ACSL isoforms 1, 4 and 6 may undergo regulation by HFD and/or exercise training. We further conclude increased skeletal muscle ACSL6 may facilitate increased intramyocellular fat storage during HFD-induced obesity.