Defective fatty acid oxidation in mice with muscle-specific acyl-CoA synthetase 1 deficiency increases amino acid use and impairs muscle function

Abstract

Loss of long-chain acyl-CoA synthetase isoform-1 (ACSL1) in mouse skeletal muscle (Acsl1M-/-) severely reduces acyl-CoA synthetase activity and fatty acid oxidation. However, the effects of decreased fatty acid oxidation on skeletal muscle function, histology, use of alternative fuels, and mitochondrial function and morphology are unclear. We observed that Acsl1M-/- mice have impaired voluntary running capacity and muscle grip strength and that their gastrocnemius muscle contains myocytes with central nuclei, indicating muscle regeneration. We also found that plasma creatine kinase and aspartate aminotransferase levels in Acsl1M-/- mice are 3.4- and 1.5-fold greater, respectively, than in control mice (Acsl1flox/flox ), indicating muscle damage, even without exercise, in the Acsl1M-/- mice. Moreover, caspase-3 protein expression exclusively in Acsl1M-/- skeletal muscle and the presence of cleaved caspase-3 suggested myocyte apoptosis. Mitochondria in Acsl1M-/- skeletal muscle were swollen with abnormal cristae, and mitochondrial biogenesis was increased. Glucose uptake did not increase in Acsl1M-/- skeletal muscle, and pyruvate oxidation was similar in gastrocnemius homogenates from Acsl1M-/- and control mice. The rate of protein synthesis in Acsl1M-/- glycolytic muscle was 2.1-fold greater 30 min after exercise than in the controls, suggesting resynthesis of proteins catabolized for fuel during the exercise. At this time, mTOR complex 1 was activated, and autophagy was blocked. These results suggest that fatty acid oxidation is critical for normal skeletal muscle homeostasis during both rest and exercise. We conclude that ACSL1 deficiency produces an overall defect in muscle fuel metabolism that increases protein catabolism, resulting in exercise intolerance, muscle weakness, and myocyte apoptosis.