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Hey everybody, it's Mikki here. You're listening to Mini Mikkipedia on a Monday. And today I am going to go a little bit deep on something I genuinely find pretty exciting. And that's that most athletes have never heard of or have heard of for completely different reasons that have a potentially compelling evidence base for performance, recovery, and long-term health. Now,

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I want to be upfront, when I talk about out of the box supplements, I don't actually mean fringe or pseudoscience. I just mean supplements that sit outside the usual conversation. Your protein powders, your creatine, your caffeine, the stuff everyone already knows about. What I want to talk about today is a layer deeper than that. Things that emerge when you actually look at what's happening metabolically inside an athlete's body under extreme load. And I want to anchor this episode in some pretty awesome research actually.

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This is a paper published in early 2026 that used the Tour de France as a kind of living laboratory. Seven elite cyclists, full metabolic profiling across the entire race. It's one of the most comprehensive looks at what excessive endurance exercise actually does to the human body at a biochemical level. I think the findings have implications far beyond professional cycling, which is clearly why I'm talking about it today. So the study itself, which we're looking at, we're working with

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cyclists from the Soudal Quick-Step cycling team. And they followed, as I said, seven elite cyclists across the entire Tour de France in 23. That's 21 stages, 3,404 kilometres and a total work output of around 75,000 kilojoules per rider. Pretty big. Blood samples were taken in the fasted state on four occasions. The morning of the first stage, the first rest day, the second rest day and the final day.

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They ran both targeted and untargeted metabolomics. So they were casting a wide net across 274 circulating metabolites. And then they just asked what changed. The headline finding was that 43 % of metabolites were significantly altered. And here's the thing that really grabbed me. The dominant direction was depletion. Wasn't elevation as you imagine with a lot of inflammation, et cetera. It's depletion. Acute exercise typically pushes these metabolites up

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as the body mobilizes fuel. But what chronic excessive endurance exercise does, according to this research, is the opposite. It draws metabolite pools down faster than the body can replenish them. And that does make sense, right, given the length of something like Tour de France. If you think about it like a bank account, cute exercise makes a large withdrawal, but recovery restores the balance. In a grand tour, there are just withdrawals upon withdrawals without the ability to replete or deposit.

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The most depleted categories were amino acids, particularly the semi-essential ones like glycine, cysteine, and proline, saturated fatty acids, specifically the less abundant ones, and acylcannitines, the intermediate molecules that shuttle fatty acids into mitochondria for burning. The most impacted metabolic pathways then were beta-oxidation of very long chain fatty acids and glutathione metabolism. Now, why does this matter for the average athlete?

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Because while you're not riding the Tour de France or probably doing anything to that extreme nature, the same pathways are being stressed just to a lesser degree. And the supplements that make sense in the context of this research are the ones that support exactly those depleted systems. And then that's what we're going to chat about. So let's start with what I think is one of the most compelling findings in the paper, really caught my attention first, and the supplement it points most directly towards. So the pathway enrichment analysis,

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which is a statistical way of asking which biochemical systems are most overrepresented among the things that changed, flagged two pathways above all others. That's beta oxidation, which we'll come back to, and glutathione metabolism.

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Glutathione is the body's master intracellular antioxidant. It's the molecule your cells use to neutralize reactive oxygen species, the damaging byproducts of energy metabolism, particularly aerobic metabolism at high intensity. And elite endurance athletes produce a lot of them. But here's the nuance. The paper didn't find that glutathione itself was depleted. What it found was that cysteine, the rate-limiting precursor for glutathione synthesis,

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was continuously and significantly depleted across all seven cyclists throughout the entire race. No plateau, no recovery on rest days, just a steady decline. And this matters because your body can only make glutathione as fast as it can source cysteine. And when cysteine runs low, your antioxidant capacity drops, which contributes to the oxidative stress that underlies many of the adverse health effects associated with excessive endurance training.

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cardiovascular remodelling, the mitochondrial dysfunction, the immune suppression. What makes this even more interesting is the second role for cysteine that the paper highlights. It's also a precursor for coenzyme A or CoA, which is essential for mitochondrial fatty acid oxidation. Recent preclinical research that's research done in mice showed that cysteine depletion actually reduces liver and muscle CoA levels, which directly leads to mitochondrial dysfunction.

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So a depleted cysteine pool could be causing problems through two completely separate pathways simultaneously. And notably, these cyclists were supplementing with antioxidants, tart cherry juice, multivitamins, the works, and cysteine still tanked, which tells you that conventional antioxidant supplementation simply wasn't adequate to meet demands. And this is exactly where N-acetylcysteine comes in, or NAC.

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NAC is a stable bioavailable form of cysteine. When you take it, it gets converted to cysteine in the body, which then feeds both glutathione synthesis and CoA production. It has a solid body of evidence in humans, including a systematic review showing it enhances endurance performance, particularly in fatigued states and improves glutathione status under oxidative stress condition. Now, this is a caveat I will always raise with NAC and with antioxidants more broadly, is the timing question. There's reasonable evidence

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that blunting oxidative stress too aggressively around training sessions can interfere with adaptation signaling. Reactive oxidative species, or ROS, aren't purely bad. They're also part of how the cells know to adapt. So the practical recommendation that emerges from the literature is to avoid taking that immediately before or after training, and instead use it at other times of the day, perhaps before bed.

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or on rest days. The goal is to support the baseline antioxidant pool without suppressing the acute training signal. The second supplement the paper points towards is Glycine. And this one tends to surprise people because Glycine sits in a bit of a biochemical no man's land. It's technically non-essential, meaning your body can make it, but it's conditionally essential, meaning that under stress, your demand can outstrip your synthesis capacity. And in the Tour de France data,

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Glycine was one of the most consistently and significantly depleted amino acids, and it has a really interesting triple role that makes it particularly compelling for athletes. First is glutathione. Glutathione is a tripeptide. Three amino acids are linked together, and those three amino acids are glutamate, cysteine, and glycine. So glycine is a co-precursor alongside cysteine for glutathione synthesis.

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when both are depleted simultaneously, as this paper shows, your body's capacity to make glutathione is constrained from two directions at once. Second, creatine. Glycine is one of the three precursors for endogenous creatine synthesis, alongside arginine and methionine. And interestingly, the paper also notes a trend towards arginine depletion after the first 10 days of racing. Both Nemvoquetel, who looked at shorter stage race, and this Tour de France paper

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found pronounced glycine decline. There's older but interesting research showing that glycine supplementation delays physical fatigue, likely through its creating supporting effects. And the third one is collagen. Glycine is the most abundant amino acid in collagen, and collagen is obviously central connective tissue. Tendons, ligaments, cartilage, et cetera. For athletes doing high volumes, connective tissue is frequently the weak link. I've already talked to

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on several podcasts about the evidence from Keith Barr's lab and others such as Mike Ornsby's lab that looked at glycine-rich collagen supplementation. with reference to Barr, timing it around training can support tendon health and potentially reduce injury risk. So glycine is simultaneously supporting your antioxidant system, your energy system, and your structural integrity. And it's cheap, well tolerated, found in high quantities in things like gelatin and bone broth, which can give you a

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both a food first and a supplement based route. Now the third supplement is Alkarnitine. Alkarnitine has a complicated reputation. It got popular as a fat burning supplement in the 90s and early 2000s. And when research didn't strongly support dramatic fat loss effects, it somewhat fell out of favor in mainstream sports nutrition circles. But I think that framing missed the more important point about what karnitine actually does.

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Carnitine is a molecule that transports acids across the inner mitochondrial membrane, so without adequate carnitine, fatty acids literally cannot enter the mitochondria to be oxidized for energy. It's not optional infrastructure, it's essential. In the Tour de France paper, alkanitine showed significant depletion, as did multiple acylcarnitine species. These are the conjugated forms that represent fatty acids in transit. The authors suggest the most likely explanation is that the rate of beta oxidization

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was so elevated that carnitine was being rapidly consumed to shuttle fatty acids into mitochondria faster than it could be recycled or replaced. Think of it like a shuttle bus system we demand completely overwhelmed swiftly. What makes the fatigue connection particularly interesting is that reduced L-carnitine and S-carnitine levels have been found in chronic fatigue syndrome, post-COVID fatigue, and cancer related fatigue. And L-carnitine supplementation has shown efficacy in attenuating

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cancer-related fatigue specifically. That paper explicitly suggests Carnitin supplementation as a strategy worth investigating for excessive exercise endurance contexts. There's also an interesting parallel to perceived fatigue in this paper. Researchers asked the cyclists to rate their fatigue on a 0 to 10 scale at each time point. It started at 0.5 at the beginning of the race and reached an 8 out of 10 by the final day. When they correlated metabolites with that fatigue score,

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carnitine-related metabolites were among those with the strongest negative associations, meaning as carnitine fell, fatigue rose. From a practical standpoint, L-carnitine supplementation has reasonable bioavailability, particularly in the L-tartrate form, and there's mechanistic logic for it that this paper reinforces. It's not a fat burner in the simplistic sense, but it may genuinely support mitochondrial function and fatigue resistance under high training loads.

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The fourth supplement that I want to mention that wasn't really a part of this paper, but it did get me thinking about other supplements athletes may consider that is not talked about in the athlete context, and that is sulforaphane. I've done a podcast interview with Dr. Christine Alton on sulforaphane, which hopefully you've listened to in the past and found it really helpful. The rationale for including it in this conversation comes from two directions meeting in the middle.

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the metabolic findings from the Tour de France paper on one side, and an environmental exposure question that I think does get nearly enough attention in the athlete context on the other. So let's explain that environmental piece first. Athletes, particularly endurance athletes, use a lot of plastic. Bidens, food pouches, gel wrappers, bottles, and these are often warm and hot. A Biden sitting in the sun during a summer ride, you know, a soft flask.

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or a gel that's been in your jersey pocket for two hours is leaching plasticizers, BPA, phthalates, and related compounds into the food or liquid you're consuming. These may not be trivial exposures. Research on cyclists specifically has found elevated urinary phthalate metabolites compared to non-athletes. These xenobiotics, foreign chemical compounds, are cleared from the body primarily via phase two detoxification enzymes in the liver. And the master regulator of these

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Enzymes is a transcription factor called nRF2. Now here's where it connects to the Tour de France paper. nRF2 also regulates the glutathione synthesis pathway, specifically the enzyme that catalyzes that rate-limiting step. So nRF2 activation simultaneously upregulates your body's capacity to clear environmental toxins and to synthesize glutathione. It's addressing the oxidative stress picture and the environmental exposure picture through the same upstream switch.

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Sulphuraphane, which comes from cruciferous vegetables, especially broccoli sprouts, is one of the most potent known NRF2 activators. There's actually human clinical trial data showing that broccoli sprout extract increases urinary excretion of benzene and other environmental chemicals, directly demonstrating the detoxification effect in real people. And there's growing sports science literature looking at NRF2 activation and exercise performance. Though sulphuraphane specifically

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is less studied in athletes than I'd like to see. The timing caveat I mentioned with NAC applies here too, and probably more strongly. NRF2 is a broad upstream activator and its antioxidant effects are potent. Taking sulforaphane acutely around training sessions could theoretically blunt that oxidative signaling that drives adaptation. This hasn't specifically been tested, but by extrapolation from the vitamin C and E literature, I'd recommend keeping sulforaphane away from training, evening, rest days,

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off-season rather than using it as a pre-workout or immediate post-workout supplement. And a practical note on sourcing sulforaphane itself, it's unstable. So many supplements actually deliver glucoraphanin, which is the precursor, which requires the enzyme morosinase to convert to the active sulforaphane. That enzyme is destroyed by cooking, which is why raw broccoli sprouts, for example, are so much more potent than cooked broccoli. Look for supplements that either include active morosinase

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provide genuine sulforaphane rather than just glucoraphanin or simply grow your own sprouts, which are cheap and surprisingly easy. So let's zoom out. What I love about these four supplements is that they're not randomly chosen. They emerge from a coherent picture of what actually happens metabolically when you push your body hard over time. That Tour de France paper essentially shows a roadmap of depletion. The glutathione pathway is overwhelmed by oxidative stress, cysteine and glycine,

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Both glutathione precursors are drained. Carnitine system is under pressure from extreme rates of fat oxidation. And all of this is happening in athletes who are already supplementing with conventional antioxidants and recovery nutrition. NAC addresses the cysteine deficit directly, feeding both glutathione synthesis and CoA production. Glycine addresses the other glutathione precursor, also supporting creatine synthesis in connective tissues. Carnitine targets the fatty acid transport

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bottleneck and has its own independent fatigue reduction evidence base, and sulforaphane works upstream of all of it, activating NRF-CAP2 to enhance the cell's own antioxidant and detoxification machinery, while also addressing the plastic exposure issue that's somewhat unique to the athlete environment. Now, none of these are magic bullets, but they're all grounded in actual biochemistry, supported by real mechanistic rationale and

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Importantly, they're addressing symptoms that conventional sports supplement recommendations largely ignore. So do you need all four? Probably not. And I'd caution against sticking everything simultaneously without some thought about your individual context. If you're an ultra endurance athlete doing high volumes in hot conditions with significant plastic exposure, sulforaphane and NAC are probably your highest priority. If your primary concern is recovery and fatigue, resistance, lysine and carnitine are where I might start.

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And if you're in a heavy training block, the timing considerations around antioxidants matter. So keep them away from your training window. And in terms of standard dosing, with NAC or N-acetylcysteine, the performance in antioxidant literature generally clusters around 12 to 1800 milligrams a day, often split into two doses. The fatigue and endurance studies tend to use about 1200. Higher acute doses have been used in some exercise studies, but GI side effects become more common.

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Hence the split dose. For athletes in heavy training blocks, 1200 milligrams in the evening is a reasonable starting point. And it is worth noting that this shouldn't be taken long term continuously without breaks. Cycling on or off or resuming at the heavy training periods is sensible. So glycine has a wide dosing range depending on the goal. The glutathione support in general recovery, three to five grams a day is well tolerated and reflects what has been used in metabolic studies. Sleep quality,

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Three grams before bed has specific randomized control trial support. And for that collagen and connective tissue, Professor Barr's lab work uses five to 15 grams of collagen or gelatin, which is about 25 to 30 % lysine by weight, taken with vitamin C about an hour before loading exercise. And I tend to say 15 grams for most people.

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So depending on your framing, that five to 15 grams standalone would cover most bases and then add your vitamin C if required. L-Carnitine, the L-Tartrate form at one to two grams a day is where most of the exercise performance literature sits. Bioavailability is genuinely enhanced when taken with carbohydrate.

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So around a meal or with carbohydrate containing recovery drink makes sense. Albeit, when I talked to Dom Dagostino about his stacks, and if you remember him, he's a professor who works in that ketogenic diet space, he actually takes about three to four grams of alkanitine, not with carbohydrate, FYI. Absorption from supplements is modest, around 14 to 18 % of an oral dose, which is why some researchers have used higher doses. So I think that's probably why Dom tends to dose a bit higher. Sulfuraphane.

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is the trickiest dose because the potency varies enormously by the source. And I would encourage you to go back and listen to Christine's podcast if you want more information. For broccoli sprout extracts, the human detoxification trials used equivalents of around 40 to 60 milligrams of sulforaphane per day. And for fresh spouts, roughly 70 to 100 grams provides that meaningful dose, though morosinase activity varies with chewing and gut microbiome.

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For standardized supplements, look for products quantifying actual sulforaphane, not just glucoraphanin, and 10 to 30 milligrams of sulforaphane equivalent is a reasonable starting range, working up to that 40 milligrams of well tolerated. GI sensitivity is the main limiting factor for some people, but if you start slow, low and slow, you can tend to unsettle down. So that's pretty much what I've got for you today. Hopefully that gave you some genuinely new things to think about, not just what to take.

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but why and what the underlying physiology actually looks like. I will put a link to the paper in the show notes and also that link to Christine Houghton's episode that I mentioned. So you can get a little bit more into the weeds if you like. And as always, hit me up with any of your questions or comments. I'm over on Instagram threads and X @mikkiwilliden Facebook @mikkiwillidennutrition. We'll head to my website, mikkiwilliden.com.

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Scroll right to the bottom and pop your name in the email box and sign up to my weekly email for more of this, but just in written form. Alright guys, you have the best week. See you later.