eNOS knock-out mice have defective mitochondrial beta-oxidation

Abstract

Objective : Recent observations indicate that the delivery of NO by endothelial nitric oxide synthase (eNOS) is not only critical for metabolic homeostasis, but could also be important for mitochondrial biogenesis, a key organelle for FFA oxidation and energy production. Because mice deficient for the gene of eNOS (eNOS-/-) have increased triglycerides and free fatty acids (FFA) levels, in addition to hypertension and insulin resistance, we hypothesized that these knock-out mice may have decreased energy expenditure and defective beta-oxidation.

Research Design and Methods : Several markers of mitochondrial activity were assessed in C57BL/6J wild-type or eNOS-/- mice including the energy expenditure and oxygen consumption by indirect calorimetry, in vitro beta-oxidation in isolated mitochondria from skeletal muscle and expression of genes involved in fatty acid oxidation.

Results : eNOS-/- mice had markedly lower energy expenditure (-10%, P<0.05) and oxygen consumption (-15%, P<0.05) than control mice. This was associated with a roughly 30% decrease of the mitochondria content (P<0.05), and most importantly, with mitochondrial dysfunction, as evidenced by a markedly lower beta-oxidation of subsarcolemmal mitochondria in skeletal (-30%, P<0.05). Finally, impaired mitochondrial beta-oxidation was associated with a significant increase of the intramyocellular lipid content (+30%, P<0.05) in gastrocnemius muscle.

Conclusions : These data indicate that elevated FFA and triglyceride in eNOS-/- mice result of defective mitochondrial beta-oxidation in muscle cells.