Skeletal Muscle Nitrate as a Regulator of Systemic Nitric Oxide Homeostasis

Abstract

Nonenzymatic nitric oxide (NO) generation via the reduction of nitrate and nitrite ions, along with remarkably high levels of nitrate ions in skeletal muscle, have been described recently. Skeletal muscle nitrate storage may be critical for maintenance of NO homeostasis in healthy aging, and nitrate supplementation may be useful for the treatment of specific pathophysiologies and for enhancing normal functions.

Time course of human skeletal muscle nitrate and nitrite concentration changes following dietary nitrate ingestion

“…However, a novel finding of the present study is the rapid uptake of NO 3 − into skeletal muscle, which was evident at 0.5 h following the ingestion of an acute bolus of KNO 3 . This highlights the speed with which NO 3 − is absorbed from the intestine into the bloodstream, transported to other tissues, and sequestered from the circulation into storage sites including muscle [ 19 ]. This process may be facilitated via the actions of sialin, a protein involved in the active transport of NO 3 − [ 29 ], which has been demonstrated to be present in skeletal muscle [ 18 , 30 ].…”

“…It is worth noting that there are challenges to the sensitive measurement of small concentrations of NO 2 − in the relatively small muscle biopsy samples that can be harvested in human volunteers compared to the whole muscles which are excised and analysed in rodent studies [ 26 ]. However, the possibility of genuine inter-species difference in muscle [NO 2 − ] should be also considered and further explored [ 19 ].…”

“…The existence of higher [NO 3 − ] in vastus lateralis muscle, compared to plasma, and its elevation following dietary NO 3 − ingestion, has recently been confirmed in humans [ 17 , 18 ]. It is possible that this relatively high muscle [NO 3 − ] has functional significance [ 19 ]. Skeletal muscle possesses the enzymatic machinery required for the reduction of NO 3 − and NO 2 − to NO (i. e., xanthine oxidoreductase, aldehyde oxidase, sulphite oxidase [ 16 ]); and it is possible that skeletal muscle serves as a NO 3 − ‘reservoir’ that might be drawn upon when access to dietary NO 3 − is restricted [ 5 , 15 ].…”

Combined Effects of Citrulline Plus Nitrate-Rich Beetroot Extract Co-Supplementation on Maximal and Endurance-Strength and Aerobic Power in Trained Male Triathletes: A Randomized Double-Blind, Placebo-Controlled Trial

“…In this sense, the sensitivity of skeletal muscle to NO 3 − availability and the dynamic changes of these, together with NO 3 − during exercise and subsequent recovery [ 65 ], certainly hint at a physiological role that has been underestimated to date, with skeletal muscle being fundamental to the maintenance of NO in the human body [ 59 , 66 ]. In fact, it has been evidenced that skeletal muscle has the capacity to accumulate, transfer and metabolize NO 3 − and nitrite [ 67 ].…”

Dietary Nitrate Supplementation Does Not Alter Exercise Efficiency at High Altitude – Further Results From the Xtreme Alps Study

“…Skeletal muscle represents a quantitatively significant site of nitrate storage ( Piknova et al, 2015 ), and its uptake from the circulation is complex ( Gilliard et al, 2018 ; Wylie et al, 2019 ). Nitrate has been proposed to act as a regulator of systemic NO homeostasis by conversion into other NO-related species ( Piknova et al, 2022 ) and may thereby confer protection against tissue damage. NO plays a key role in enabling oxygen and nutrient delivery by improving blood flow, and also in matching energy supply with demand by modulating mitochondrial function and intermediary metabolism ( Umbrello et al, 2013 ).…”