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NOS3 is involved in the increased protein and arginine metabolic response in muscle during early endotoxemia in mice

Departments of ¹Surgery and ²Anatomy and Embryology, Nutrition and Toxicology Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands

Submitted 13 October 2004 ; accepted in final form 5 January 2005

Sepsis is a severe catabolic condition. The loss of skeletal muscle protein mass is characterized by enhanced release of the amino acids glutamine and arginine, which (in)directly affects interorgan arginine and the related nitric oxide (NO) synthesis. To establish whether changes in muscle amino acid and protein kinetics are regulated by NO synthesized by nitric oxide synthase-2 or -3 (NOS2 or NOS3), we studied C57BL6/J wild-type (WT), NOS2-deficient (NOS2^–/–), and NOS3-deficient (NOS3^–/–) mice under control (unstimulated) and lipopolysaccharide (LPS)-treated conditions. Muscle amino acid metabolism was studied across the hindquarter by infusing the stable isotopes L-[ring-²H₅]phenylalanine, L-[ring-²H₂]tyrosine, L-[guanidino-¹⁵N₂]arginine, and L-[ureido-¹³C,²H₂]citrulline. Muscle blood flow was measured using radioactive p-aminohippuric acid dilution. Under baseline conditions, muscle blood flow was halved in NOS2^–/– mice (P < 0.1), with simultaneous reductions in muscle glutamine, glycine, alanine, arginine release and glutamic acid, citrulline, valine, and leucine uptake (P < 0.1). After LPS treatment, (net) muscle protein synthesis increased in WT and NOS2^–/– mice [LPS vs. control: 13 ± 3 vs. 8 ± 1 (SE) nmol·10 g^–1·min^–1 (WT), 18 ± 5 vs. 7 ± 2 nmol·10 g^–1·min^–1 (NOS2^–/–); P < 0.05 for LPS vs. control]. This response was absent in NOS3^–/– mice (LPS vs. control: 11 ± 4 vs. 10 ± 2 nmol·10 g^–1·min^–1). In agreement, the increase in muscle arginine turnover after LPS was also absent in NOS3^–/– mice. In conclusion, disruption of the NOS2 gene compromises muscle glutamine release and muscle blood flow in control mice, but had only minor effects after LPS. NOS3 activity is crucial for the increase in muscle arginine and protein turnover during early endotoxemia.

nitric oxide; nitric oxide synthase; metabolism; sepsis

This article has been cited by other articles:

				C. H. Lang, R. A. Frost, and T. C. Vary Regulation of muscle protein synthesis during sepsis and inflammation Am J Physiol Endocrinol Metab, August 1, 2007; 293(2): E453 - E459. [Abstract] [Full Text] [PDF]