The tortuous path of lactate shuttle discovery: From cinders and boards to the lab and ICU

Abstract

Highlights In the 2019 American College of Sports Medicine Wolffe lecture George Brooks described history Lactate Shuttle development. Lactate is a fuel energy source, the main gluconeogenic precursor, and a signaling molecule with autocrine, paracrine, and endocrine functions. Endurance training develops the capacities to produce, remove and utilize lactate. Lactate is favored as a fuel by working red muscle, heart, liver, and brain. Clinical trials are under way to improve outcomes in traumatic brain injury patients using lactate supplementation. The importance of Lactate Shuttle in normal physiology is emphasized by the realization that dysfunctional lactate shuttling is involved in cancer, metabolic inflexibility, and inflammation.

The anaerobic threshold: 50+ years of controversy

“…Numerous studies over the intervening period have shown that La − is not merely a dead‐end waste product of anaerobic metabolism, but is instead a continuously produced and removed metabolite that circulates among and within essentially all cells of the body (Brooks, 2018). Both the evidence and the concept have been extensively reviewed previously (Gladden, 1996, 2004 a , b , 2008; Brooks, 2000, 2002, 2007, 2009, 2016, 2018, 2020 b ; Brooks & Gladden, 2003), and the reader is referred to those summaries.…”

“…Originally conceived as a means to shuttle reducing equivalents among cells, tissues and organs, we now know that La − shuttling fulfils three basic functions: (1) La − is a major, sometimes preferred, energy substrate; (2) La − is the primary gluconeogenic precursor; and (3) La − is a signalling molecule (Brooks, 1986(Brooks, , 2018(Brooks, , 2020b. Workers in diverse fields such as brain metabolism, sepsis, cancer and diabetes research, are employing lactate shuttle theory in an effort to better understand normal and disrupted metabolism in different tissue and cell types.…”

Lactate in contemporary biology: a phoenix risen

“…So far as mitochondrial pyruvate transport and oxidation are concerned, it is known that the putative mPC colocalizes with mitochondrial MCT1 in L6 myocytes. In preliminary studies, colocalization analysis of mMCT1 and mPC1 using Imaris software revealed that both MCT1 and mPC are co-localized to the mitochondria (r 2 = 0.8) (Brooks, 2020c). However, because muscle lactate concentration exceeds that of pyruvate by one (10x) to two (200-400x) orders of magnitude in resting and exercising human muscles, respectively (Henderson et al, 2004), lactate oxidation is dominant in vivo.…”

“…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 Ferguson et al, 2018;Brooks, 2020c). Conflation of the terms perpetuates the myth of lactate poisoning and thus handicaps understanding of basic biology and its translation.…”

Commentary on “The tortuous path of lactate shuttle discovery: From cinders and boards to the lab and ICU”

“…It is a pleasure to provide a commentary on the outstanding review 1 by Dr. George Brooks that discusses both the discovery and importance of the lactate shuttle. Clearly, Professor Brooks is highly qualified to review this important topic.…”