Lactate in contemporary biology: a phoenix risen

Abstract

After a Century, it's time to turn the page on understanding of lactate metabolism and appreciate that lactate shuttling is an important component of intermediary metabolism in vivo. Cell-Cell and intracellular Lactate Shuttles fulfill purposes of energy substrate production and distribution as well as cell signaling under fully aerobic conditions. Recognition of lactate shuttling came first in studies of physical exercise where the roles of driver (producer) and recipient (consumer) cells and tissues were obvious. Moreover, the presence of lactate shuttling as part of postprandial glucose disposal and satiety signaling has been recognized. Mitochondrial respiration creates the physiological sink for lactate disposal in vivo. Repeated lactate exposure from regular exercise results in adaptive processes such as mitochondrial biogenesis and other healthful circulatory and neurological characteristic such as improved physical work capacity, metabolic flexibility, learning, and memory. The importance of lactate and lactate shuttling in healthful living is further emphasized when lactate signaling and shuttling are dysregulated as occur in particular illnesses and injuries. Like a Phoenix, lactate has risen to major importance in 21 st Century Biology.

Role of the Heart in Lactate Shuttling

“…For instance, during exercise, fast white fibers can provide oxidizable substrate to red, oxidative fibers in the same tissue bed (22,30). Conversely, postprandial glucose uptake in red fibers can provide substrate to the body corpus as in the glucose paradox (31) and postprandial lactate shuttle (32). By means of lactate shuttling, working muscle can fuel the beating heart (28), support cerebral executive functions (33)(34)(35)(36)(37)(38)(39), and provide gluconeogenic precursor to the splanchnic organs (40,41).…”

Beyond the Lactate Paradox: How Lactate and Acidity Impact T Cell Therapies against Cancer

“…The biology of lactate metabolism is highly complex, and its immune-suppressive attributes may be limited to hypoxic conditions. As a fuel, lactate oxidation supports ATP replenishment in neurons [ 9 ], skeletal myofibers [ 10 ] and some tumor cells [ 11 ]. Lactate has important roles in metabolism beyond energy production.…”

Exercise Training and Circulating Small Extracellular Vesicles: Appraisal of Methodological Approaches and Current Knowledge

“…A small number of molecules may decrease in abundance in response to acute exercise, but it is generally considered that the majority of changes in exercise factors are in the form of increased circulating abundance(s; Fernández-Sanjurjo et al, 2018;Son et al, 2018;Murphy et al, 2020;Severinsen and Pedersen, 2020). Some individual factors are well-described and understood in terms of the kinetics of their response to exercise and subsequent metabolic and/or molecular effects, such as the metabolite lactate (van Hall, 2010;Brooks et al, 2021), and the myokine interleukin-6 (IL-6; Pedersen and Febbraio, 2008). Mention of the latter molecule is of particular importance as an illustration of a prototypical exercise factor.…”