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 fulfil purposes of energy substrate production and distribution, as well as cell signalling 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 signalling 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 characteristics 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 signalling and shuttling are dysregulated as occurs in particular illnesses and injuries. Like a phoenix, lactate has risen to major importance in 21st century biology.

Keywords: exercise; fibre type; gene adaptation; gluconeogenesis; glycogenolysis; indirect pathway; lactate shuttle; lactate signalling; microbiome; muscle; postabsorptive metabolism; postprandial metabolism; satiety.

Figure 1. The concept of lactate shuttling between producer (driver) cells and tissues and consumer (recipient)

By this mechanism lactate has autocrine‐, paracrine‐ and endocrine‐like influences on metabolism that fulfil at least three purposes. Lactate is: (1) a major energy source; (2) the major gluconeogenic precursor; and (3) a signalling molecule. Revised from Brooks (2018).

Figure 2. Illustration of lactate shuttling during exercise (the cell‐cell lactate shuttle)

Lactate released from muscles, skin and other driver cells provides energy for working muscles (Stanley et al. ; Bergman et al. b), heart (Gertz et al. , ; Bergman et al. b) and brain (Glenn et al. a). Moreover, lactate released from working muscles (Stanley et al. ; Bergman et al. b) and other driver cells such as adipose tissue is the major gluconeogenic precursor (Stanley et al. ; Bergman et al. 2000) and brain fuel, even after injury when lactate supplementation may be efficacious (Brooks & Martin, 2014). Revised from Brooks (2018).

Figure 3. Illustration of lactate shuttling after consuming dietary carbohydrate: the postprandial period (the postprandial lactate shuttle)

Depending on liver glycogen content some dietary glucose bypasses liver and enters the systemic circulation. From there glucose is taken up by non‐contracting muscles, particularly red and intermediate fibres (James et al. 1985, 1986). Glycolysis in these and other driver tissues results in lactate release into the central venous circulation and uptake by the recipient liver from the arterial circulation. Paradoxically, this circuitous, ‘indirect pathway,’ is preferred over glucose for hepatic glycogen synthesis (Foster, 1984). In contrast, glucose from dietary consumption or digestion or carbohydrate in the GI tract can be taken up by liver on the first circulatory pass for ‘direct’ glycogen synthesis. Again as indicated in Fig. 2, lactate released from driver cells and tissues supports cerebral metabolic needs (Glenn et al. a, b ) and functions such as glutamatergic signalling (Pellerin & Magistretti, 1994). Similarly, systemic lactate and fatty acids from digestion serve as an energy source for the heart (Bergman et al. 2009a,b). Figures 2 and 3 illustrate the extent of lactate shuttling under diverse conditions.