Thread by @mitokanedria

“...Time is the fire in which we burn.” -Delmore Schwartz

🪡 🧵 thread about #lactate oxidation and metabolic heat 🔥. /1

frontiersin.org/articles/10.33…

The story begins at least ~300k years ago when early modern humans first appear on the scene. As detailed in @HermanPontzer’s Burn (2021), humans are the best endurance athletes among the living apes:

VO2max >4x that of chimps
⬆️proportion of “slow twitch” skm fibers

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⬆️hemoglobin in blood 🩸
Naked, sweaty skin ➡️ helps protect against overheating, e.g., when exercising in hot temps

BUT...

Humans have notably big brains, which are metabolically expensive. /3

An adult brain may weigh just <3 lbs, but account for some 20% of BMR.

What’s a brain to do when heat threatens homeostatic body temps?

⬆️ blood flow and volume!

But what if the core:brain gradient ⬇️, as with prolonged or intense exercise in the heat? /4

In 1923, BFFs A.V. Hill and Otto Meyerhof split the Nobel Prize in Physiology or Medicine for their discoveries relating to the production of heat in muscle (Hill), and the relationship between oxygen consumption and lactate metabolism in muscle (Meyerhof). /5

Hill’s work indicated that the consumption of lactate by muscle cells yielded far less heat than expected for complete oxidation of lactate. The prevailing interpretation was that only a minor fraction of the lactate undergoes complete oxidation /6

intechopen.com/chapters/53367

This view was revised for mammalian metabolism vis-a-vis @GeorgeABrooks3’s Lactate Shuttle model. First conceived by Brooks (1985), a central tenet of the model was that lactate travels within and between cells as an oxidizable fuel /7

link.springer.com/chapter/10.100…

While research has increasingly confirmed Brooks’ model and the centrality of lactate metabolism (e.g., pubmed.ncbi.nlm.nih.gov/29045397/ @realTonyHui), work on the physical bioenergetics of lactate metabolism has been relatively sparse since the time of Hill & Meyerhof. /8

What of Hill’s “missing heat”? Textbook: “glycogen resynthesis”.
But, one of his contemporaries, J.K. “golden eye” Parnas saw ⬆️ lactate oxidation in muscle with prolonged (20 hrs) recovery. These results were later dismissed. /9

nature.com/articles/17553…
annualreviews.org/doi/pdf/10.114…

In the last reaction of glycolysis, pyruvate is reduced to lactate, and the greatest amount of heat is release in the pathway. Reversing the reaction (i.e., lac to pyr) should consume heat. Does this mean lactate oxidation consumes heat?! /10

pubmed.ncbi.nlm.nih.gov/7451/

Scott & Kemp aimed to answer this question using both direct (heat rate) and indirect (oxygen consumption) calorimetry to compare the heat/O2 in permeabilized tissue (heart) and cells fed lactate vs pyruvate. Their answer: no, the heat/O2 is similar. /11

pubmed.ncbi.nlm.nih.gov/15841591/

HOWEVER,

The cofactor (NAD+) for lac oxidation to pyr was not added, and the MitoCarta inventory of mitochondrial proteins does not indicate a mito matrix location for L-lactate dehydrogenase in heart. This suggests NAD+ should have been added. /12

broadinstitute.org/mitocarta/mito…

We measured heat rate and O2 consumption rate in permeabilized brain samples. The heat/O2 with pyruvate was as expected, but the heat/O2 with lactate (+NAD+) was surprisingly low - lower even than predicted by Thornton’s Rule. /13

frontiersin.org/articles/10.33…

Thornton’s Rule states that the heat of combustion of organic compounds per mol O2 is relatively constant. In our case, the heat/O2 below the oxycaloric ratio for lactate according to Thornton’s Rule implies a level of incomplete oxidation of lactate /14

tandfonline.com/doi/abs/10.108…

If complete lactate oxidation is divided into 3 reactions:

1. Lac ➡️ Pyr + NADH
2. Lac + 0.5O2 ➡️ Pyr + H2O
3. Pyr + 2.5O2 ➡️ 2CO2 + H2O

The low heat/O2 with lactate may be explained by reaction 1 outpacing reactions 2 and/or 3.

/15

How this is achieved was not investigated experimentally, but the literature has some clues. Namely, reports that L-lactate partially inhibits the oxidation of pyr (though this finding is not universal). /16

pubmed.ncbi.nlm.nih.gov/35181821/
pubmed.ncbi.nlm.nih.gov/22296683/
pubmed.ncbi.nlm.nih.gov/33035451/

The submitochondrial location of LDH could theoretically impact the heat/O2...

/17

But we didn’t explore the submitochondrial location of LDH. The topic has received some attention recently (links below). /18

ncbi.nlm.nih.gov/pmc/articles/P…
pubmed.ncbi.nlm.nih.gov/32916028/
pubmed.ncbi.nlm.nih.gov/31610469/
pubmed.ncbi.nlm.nih.gov/32358865/
pubmed.ncbi.nlm.nih.gov/34884425/
pubmed.ncbi.nlm.nih.gov/36075947/

Brain temp is mainly dictated by core body and arterial temps. Prolonged exercise with hyperthermia poses a problem for the 🧠 . Cerebral oxygenation due to blood flow incr during exerc, but the cerebral metabolic ratio of O2/[glucose+0.5lactate] ⬇️

/19

pubmed.ncbi.nlm.nih.gov/22125311/

The ⬇️ in 🧠 O2/[glucose+0.5lactate] with exerc has been interpreted to reflect declining complete oxidation but not accumulation of glucose and lactate taken up by the 🧠. /20

ncbi.nlm.nih.gov/pmc/articles/P…

Incidentally, muscle glycogen breakdown and lactate release is ⬆️ with exercise in the heat. Muscle temps and epinephrine are thought to be among the mechanisms responsible. /21

pubmed.ncbi.nlm.nih.gov/17720623/

As a primary stress mediator, the regulation of epinephrine secretion is a example of allostasis - a term coined by @whatishealth21 and Eyer (1988) to refer to physiologic stability through variation. (✅ out the excellent book What is Health? 2020). /22

worldcat.org/en/title/17234…

Thus, allostasis serves homeostasis, a key parameter of which is stable core temps in homeotherms. If lactate metabolism is an allostatic mediator of metabolic heat, is this reflected in training adaptations to exercise in the heat? Yes. /23

1. A ⬇️ in metabolic heat prod has been observed with acclimation to exerc in heat.
2. ⬇️ in lactate accumulation. /24

onlinelibrary.wiley.com/doi/abs/10.111…

3. ⬆️ aerobic fitness itself is among the best means of mitigating hyperthermic effects of exerc in heat.

The typical ⬆️ in LT with endurance training are mainly due to ⬆️ rates of lactate clearance. /25

frontiersin.org/articles/10.33…
pubmed.ncbi.nlm.nih.gov/23558389/

The therapeutic use of IV lactate seems to benefit especially TBI patients.

BUT see also the recent work of @jens_lund et al!

Of note: syst hyperthermia is common in TBI patients, and may even cause 2ndary 🧠 injury.

/26

pubmed.ncbi.nlm.nih.gov/35304646/

pubmed.ncbi.nlm.nih.gov/37055619/

A recent study by Okahashi et al implicates the ⬇️ metabolic heat as an explanation of cancer cells’ reliance on glycolysis vis-a-vis the Warburg effect. /27

biorxiv.org/content/10.110…

& there’s evidence for lactate shuttling in cancer cells /28

pubmed.ncbi.nlm.nih.gov/19033663/

frontiersin.org/articles/10.33…

Whole-body and localized-regional hyperthermia has been used as a cancer treatment alone or in combo with others. /29

ncbi.nlm.nih.gov/pmc/articles/P…

TL;DR we found the rate of heat production in lactate-fed mitochondria to be intriguingly low in mammalian brain, and suggest a model in which lactate serves a thermoregulatory function in the 🧠.

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frontiersin.org/articles/10.33…

TL;DR;DRTL;DR “I’d rather be clearing #lactate” 👟

/31

Shout out to collab’s Alex Foo, Erin Noftall, Karen Brebner, and @gmsprezman

And to the helpful reviewers, one of whom (revealed later to be THE Lee Hansen) provided exceptional feedback and guidance.

✌️/fin