Increasing muscle mass improves vascular function in obese (db/db) mice

Background A sedentary lifestyle is an independent risk factor for cardiovascular disease and exercise has been shown to ameliorate this risk. Inactivity is associated with a loss of muscle mass, which is also reversed with isometric exercise training. The relationship between muscle mass and vascular function is poorly defined. The aims of the current study were to determine whether increasing muscle mass by genetic deletion of myostatin, a negative regulator of muscle growth, can influence vascular function in mesenteric arteries from obese db/db mice. Methods and Results Myostatin expression was elevated in skeletal muscle of obese mice and associated with reduced muscle mass (30% to 50%). Myostatin deletion increased muscle mass in lean (40% to 60%) and obese (80% to 115%) mice through increased muscle fiber size ( P NO ) synthase inhibitor l ‐ NG ‐nitroarginine methyl ester ( l ‐ NAME) . Prostacyclin ( PGI 2 )‐ and endothelium‐derived hyperpolarizing factor ( EDHF)‐ mediated vasodilation were preserved in obese mice and unaffected by myostatin deletion. Reactive oxygen species) was elevated in the mesenteric endothelium of obese mice and down‐regulated by deletion of myostatin in obese mice. Impaired vasodilation in obese mice was improved by NADPH oxidase inhibitor ( GKT 136901). Treatment with sepiapterin, which increases levels of tetrahydrobiopterin, improved vasodilation in obese mice, an improvement blocked by l ‐ NAME . Conclusions Increasing muscle mass by genetic deletion of myostatin improves NO‐ , but not PGI 2 ‐ or EDHF‐ mediated vasodilation in obese mice; this vasodilation improvement is mediated by down‐regulation of superoxide.