Lactate in contemporary biology: a phoenix risen - PubMed
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...
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Introduction
The story of lactate and its role in physiology and medicine may be a century old, but has changed dramatically in the last three decades (Brooks, 1986, 2002, 2018; Gladden, 2004). No longer conceived of as a dead-end metabolite, a fatigue agent, or metabolic poison, in contemporary physiology, lactate is seen as a major metabolic intermediate that has wide ranging impacts in energy substrate utilization, cell signalling, and adaptation; simply, lactate is at the fulcrum of metabolic integration (Brooks, 1984, 1986, 2020a). Now, rather than regarded as an oddity of exercise metabolism (Gladden, 2004; Chen et al. 2016; Hui et al. 2017; Brooks, 2018; Ferguson et al. 2018), the presence of lactate shuttling is recognized in fields as diverse as wound healing (Hunt et al. 2007), cancer biology (San-Millan & Brooks, 2017), insulin secretion (Rutter et al. 2015), management of sepsis (Garcia-Alvarez et al. 2014a), learning and memory (Suzuki et al. 2011; El Hayek et al. 2019), and treatment of traumatic brain injury (TBI) (Brooks & Martin, 2014). Hence, in contemporary biology, the role of lactate in metabolism needs to be understood and viewed as a ‘phoenix risen’ (Brooks, 2002, 2018) in contrast to a remnant of (1988) early 20th century biology (Rabinowitz & Enerback, 2020).As scholars we have our limitations and, as a consequence, in formal education we rely on tradition to a certain extent despite obvious evidence to the contrary. Commencing with work of early 20th century Nobel prize winners (Hill, 1914; Meyerhof, 1920), the role of lactate in metabolism has been misunderstood and perpetuated. Even as their cell and tissue cultures incubated in air often turned acidic overnight, textbook authors (e.g. Lehninger, 1970) perpetuated the myth of oxygen-limited metabolism giving rise to lactate formation despite the fact that the partial pressure of oxygen in air over their mitochondrial preparations and culture dishes was 3–5 times higher than in vivo (Brooks et al. 2019). Hence, a reckoning of minds in biology is necessary to understand human and mammalian metabolism in a contemporary context.
Take for instance conflations of terms ‘glycolysis’ and ‘fermentation.’ In mammalian tissues, glycolysis (i.e. conversion of glucose and glycogen to lactate) is very different from aerobic fermentation of sugar to alcohol by yeast, or the production of swamp gases by anaerobic bacteria as occurs in the colon, at wound sites or in rotting (Brooks, 2018, 2020c; Ferguson et al. 2018). Conflation of the terms perpetuates the myth of lactate poisoning and thus handicaps understanding of basic biology and its translation. Fortunately, textbook authors are noting a distinction between glycolysis as occurs in animals in vivo, and fermentation processes that occur in microbes giving rise to ethanol and foul gases (Urry et al. 2020).
Lactate metabolism in injuries and illnesses
This issue has been addressed in recent reviews (Brooks, 2018, 2020a), but there appear to be both positive and negative aspects to lactate metabolism in illnesses and injuries (Table 1).Table 1. Potential for lactate treatment for illness and injury (from Brooks, 2020a)
| Resuscitation (fluid, electrolytes, energy) (Azevedo et al. 2007; Garcia-Alvarez et al. 2014a; Marik & Bellomo, 2016) |
| Acidosis (exogenous lactate infusion has an alkalotic effect) (Miller et al. 2005; Wu et al. 2011; Marik & Bellomo, 2016) |
| Regulation of glycaemia (lactate is the major gluconeogenesis (GNG) precursor) (Meyer et al. 1998, 2002; Gerich et al. 2001; Marik, 2009) |
| Traumatic brain injury (lactate is brain fuel and anti-inflammatory) (Glenn et al. 2015a) |
| Inflammation (via GPR81 binding down stream signalling lactate inhibit the inflammasome) (Hoque et al. 2014) |
| Acute pancreatitis and hepatitis (lactate is an energy substrate, a GNG precursor and anti-inflammatory agent) (Hoque et al. 2014) |
| Myocardial infarction, cardiac surgery and acute heart failure (lactate is heart fuel) (Shapiro et al. 2005; Bergman et al. 2009b) |
| Burns (lactate is an energy substrate, a GNG precursor and anti-inflammatory agent) (Spitzer, 1979) |
| Sepsis (lactate incorporation in resuscitation fluids can support maintenance of blood pressure and circulation, and help deliver antibiotics, as well as being an energy substrate, a GNG precursor and have an anti-inflammatory effect) (Garcia et al. 1995; Marik & Bellomo, 2016) |
| Dengue (lactate is an energy substrate, a GNG precursor and anti-inflammatory agent) (Wu et al. 2011; Somasetia et al. 2014) |
| Cognition (lactate readily crosses the blood-brain barrier, fuels neurons and stimulates secretion of brain-derived neurotrophic factor (BDNF), improves executive function and memory) (Rice et al. 2002; Holloway et al. 2007; Hashimoto et al. 2018) |
| Wound healing (Hunt et al. 2007) and muscle regeneration after injury (Tsukamoto et al. 2018; Ohno et al. 2019). |
Lactate controls lipid metabolism: the role of lactate in metabolic flexibility and the crossover concept
Lactate from working muscle (Bergman et al. 1999b) or other tissues such as the integument (Johnson & Fusaro, 1972) has short-term effects on lipid metabolism by downregulating both lipolysis and mitochondrial free fatty acid entry and oxidation. In contrast, chronic exercise exposure, as with endurance training, improves capacities to maintain glycaemia and lipid oxidation by improving the ability to clear lactate by oxidation (Bergman et al. 1999b) and gluconeogenesis (Bergman et al. 2000), as well as acting as a pseudo-myokine (Takahashi et al. 2019) (vide infra). The role of lactate in affecting energy substrate partitioning in exercise and other conditions is imbedded in concepts of ‘crossover’ (Brooks & Mercier, 1994) and metabolic flexibility (Kelley et al. 1999; Goodpaster & Sparks, 2017; San-Millan & Brooks, 2018). In the case of lactate and lipolysis in adipose tissue, during hard exercise inverse relationships between blood lactate and plasma free fatty acid concentration [FFA] in humans (Brooks & Mercier, 1994) and other mammals (Issekutz & Miller, 1962; Rodahl et al. 1964) have long been recognized. Also, lactate infusion into running dogs caused the circulating [FFA] to decline (Issekutz & Miller, 1962; Gold et al. 1963; Miller et al. 1964). In those investigations an effect of lactate on circulating [FFA] could be clearly observed, but whether the mechanisms involved hydrogen ions or lactate anions was not assessed.The mechanism by which lactataemia suppresses circulating FFAs is now known to be due to suppression of adipose lipolysis by lactate binding to hydroxycarboxylic acid receptor 1 (HCAR-1), formerly known as G-protein coupled receptor 81 (GPR-81), independently of changes in pH (Cai et al. 2008; Ge et al. 2008; Liu et al. 2009; Ahmed et al. 2010). Signalling effects of lactate on HCAR-1 are further discussed below.
Summary
Time is overdue to turn the page on understanding lactate metabolism and consider lactate shuttling as an important component of intermediary metabolism in vivo. Lactate shuttling between producer (driver) and consumer (recipient) cells requires the presence of cell-cell and intracellular lactate shuttles that fulfil at least three purposes; lactate is: (1) a major energy source, (2) the major gluconeogenic precursor and (3) a signalling molecule. There is little or no evidence for oxygen inadequacy giving rise to lactate production and accumulation in resting or exercising subjects, even in the hypoxia of high altitude (Brooks et al. 1991). Rather, there is abundant evidence that lactate production occurs in fully aerobic tissues and organs (Gertz et al. 1981; Stanley et al. 1985; Richardson et al. 1998; Park et al. 2015). Recognition for lactate shuttling came first in studies of physical exercise where roles of driver and recipient cells were obvious. However, simultaneously and independently the presence of lactate shuttling as part of postprandial glucose disposal was recognized in studies of lab animals (Foster, 1984) and humans (Woerle et al. 2003). Importantly, lactate (not pyruvate) enters the mitochondrial reticulum to support cell energy homeostasis by oxidative phosphorylation of ADP and creatine (Hashimoto et al. 2006). Hence, mitochondrial respiration creates the physiological sink for lactate disposal in vivo. As research progresses important facets of lactate shuttling are becoming recognized with regard to cell signalling and metabolic regulation (Brooks, 2020a).In diverse tissues lactate acts by mass action, cell redox regulation, ROS generation, allosteric binding and lactylation of histones. By inhibiting lipolysis in adipose tissue, via HCAR-1 binding and CREB activation, and muscle mitochondrial fatty acid uptake, via malonyl-CoA and CPT1, lactate controls lipid oxidation and overall energy substrate partitioning. 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 (Brooks, 2018), memory and cognition (Suzuki et al. 2011; El Hayek et al. 2019). The importance of lactate and lactate shuttling in healthful living is further emphasized when lactate signalling and shuttling are dysregulated as occur in cancer (San-Millan & Brooks, 2017) and other conditions such as following traumatic brain injury (Glenn et al. 2015b), metabolic syndrome (Brooks, 2018; San-Millan & Brooks, 2018), inappropriate insulin signalling (Rutter et al. 2015) and sepsis (Garcia-Alvarez et al. 2014a). While much has been done to determine energetic regulation in steady and transient states of metabolism, the importance of measuring the dynamics of metabolism beyond stagnant use of ‘metabolomics’, by assessing physiological, environmental and age-related effects on the turnover rates of lactate, glucose, fatty and amino acids as well as structural and metabolic proteins and membranes (i.e. ‘fluxomics’), are research challenges for the new millennium.
