Oral administration of l-citrulline alters the vascular delivery of substances to rat skeletal muscles

Abstract

Vascular endothelial function deteriorates with age and disease, and the production of vasodilator factors like nitric oxide (NO) decreases. The free amino acid l -citrulline increases vasodilation and blood flow through increased NO production. We examined the effects of oral l -citrulline administration on vascular delivery of substances to skeletal muscles. In Experiment 1, following oral l -citrulline administration and subsequent intravenous Evans blue dye (EBD) administration to rats, EBD levels delivered to skeletal muscles were measured after 60 min. In Experiment 2, plasma concentrations of amino acids and NOx, an indicator of vasodilation, were measured over time after oral l -citrulline administration. In Experiment 3, we measured EBD levels in skeletal muscles of streptozotocin-induced type 1 diabetic rats following l -citrulline administration. In these experiments, EBD levels in the soleus muscle were higher in the l -citrulline group than in the control group (19.9 ± 0.7 vs. 22.5 ± 1.9 μg/g tissue, p < 0.05). Plasma l -arginine, l -citrulline, and NOx levels were increased within 30 min after l -citrulline administration. EBD levels in the soleus and gastrocnemius muscles were higher in diabetic rats with l -citrulline administration (18.7 ± 2.2 vs. 25.0 ± 4.3 μg/g tissue, p < 0.05 and 8.0 ± 0.5 vs. 9.2 ± 0.8 μg/g tissue, p = 0.05, respectively). These data suggest that oral l -citrulline administration may increase the level of substances delivered to skeletal muscles by increasing the NO production in both normal and vascular endothelial dysfunction models.

Association of endothelial dysfunction and peripheral arterial disease with sarcopenia in chronic kidney disease

“…The maintenance of skeletal muscle health is determined by the balance of synthesis and breakdown of skeletal muscle protein, which partially depends on the integrity of skeletal muscle microcirculation. Endothelial dysfunction reduces muscle protein synthesis by compromising the delivery of nutrients into skeletal muscles and hampering their utility, 8 , 9 , 10 , 22 whereas ischaemia and reperfusion injury resulting from lower extremity atherosclerosis accelerate muscle protein degradation through mitochondria dysfunction, enhancement of reactive oxygen species and oxidative stress and activation of inflammatory and the transforming growth factor‐beta (TGF‐β) pathway. 11 , 23 Observational studies have reported a close relationship between endothelial dysfunction or PAD and sarcopenia in various populations.…”

“…Previous experimental studies have established the critical role of endothelium‐regulatory vasodilatation on amino acid delivery into skeletal muscle and protein anabolism, whereas blunted vasodilatation results in anabolic resistance. 8 , 9 , 10 Moreover, atherosclerosis of the lower extremities, a characteristic of peripheral arterial disease (PAD), induces skeletal muscle ischaemia and reperfusion injury, resulting in impaired mitochondrial function and enhanced inflammation and oxidative stress. 11 Unfortunately, despite the frequency of endothelial dysfunction, atherosclerosis and sarcopenia in patients with CKD, their interrelationships remain largely unexplored.…”

“…Given the high degree of vascularization of skeletal muscle, disturbances in skeletal muscle microperfusion resulting from atherosclerosis and endothelial dysfunction may be involved in the pathogenesis of sarcopenia in patients with CKD. Previous experimental studies have established the critical role of endothelium‐regulatory vasodilatation on amino acid delivery into skeletal muscle and protein anabolism, whereas blunted vasodilatation results in anabolic resistance 8–10 . Moreover, atherosclerosis of the lower extremities, a characteristic of peripheral arterial disease (PAD), induces skeletal muscle ischaemia and reperfusion injury, resulting in impaired mitochondrial function and enhanced inflammation and oxidative stress 11 .…”

Combined L-Citrulline Supplementation and Slow Velocity Low-Intensity Resistance Training Improves Leg Endothelial Function, Lean Mass, and Strength in Hypertensive Postmenopausal Women

“…Endothelial dysfunction has been proposed as a mechanism of reduced muscle mass and strength in older women [ 5 , 6 ]. The possible mechanism is that CIT, as a precursor of de novo plasma ARG, enhances peripheral vasodilation via greater ARG-NO bioavailability [ 33 , 58 , 61 ] leading to greater delivery of nutrients, insulin, and oxygen to skeletal muscles [ 62 ]. Moreover, CIT supplementation directly stimulates muscle protein synthesis, which may contribute to improve muscle mass and strength in a malnourished state and sedentary aging [ 21 , 63 ].…”

Metabolic effects of L‐citrulline in type 2 diabetes

“…Furthermore, rates of Cit conversion to Arg 85–87,90 and Arg conversion to Cit 85–87 are also higher in rodents. Differences have also been reported between rats and mice; male rats have higher serum Cit (64.6 ± 7.8 109 and 70.0 ± 8.0 110 vs 40 ± 5 85 μM) and plasma Cit flux (197 ± 11 80 vs 95.4 ± 29.1 85 and 81.1 ± 4.7 80 μmol/kg/h) than male mice. Furthermore, a higher rate of NO production was reported in mice (7.68 ± 1.47 μmol/kg/h) than in rats (0.55 ± 0.05 μmol/kg/h) 111 …”