Lost Metabolic Machinery During Ketosis? Depends Where You Are Looking : Strength & Conditioning Journal

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Letter to the Editor

Lost Metabolic Machinery During Ketosis? Depends Where You Are Looking

Wood, Thomas BM BCh, PhD1,2

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Strength and Conditioning Journal 39(5):p 94-95, October 2017. | DOI: 10.1519/SSC.0000000000000322
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To the Editor:

I read with great interest the recent point/counterpoint article on the ketogenic diet (KD) for athletes (5). As the application of the KD will depend on a number of factors, especially the athlete's goals and chosen sport, the well-balanced viewpoints displayed in the article are essential. However, although a number of studies show great promise, the assertion that “the beneficial effects of a KD on aerobic performance are fairly well established” still remains slightly premature. In general, the point raised by Dr. Nelson—that “well-rounded athletes should possess the ability to use all fuel substrates effectively”—is an important one. Rather than sticking to a strict KD, periodization of carbohydrate intake around training and performance goals is likely to be the best approach for the majority of athletes (4,6). That being said, deciding whether somebody is lacking any metabolic machinery as a result of the KD will depend on degree of adaptation to the diet and the outcomes or markers being measured.

As mentioned in the counterpoint, the capacity to perform glycolysis is often assessed by measuring the activity of pyruvate dehydrogenase (PDH), which is the last step of glycolysis that converts pyruvate to acetyl-CoA to enter into the Krebs cycle. However, there are a number of enzymatic steps between blood glucose (or muscle glycogen) and pyruvate that may not be suppressed by the KD. The best example of this is the study by Volek et al. cited by both sides in the original article (8). In that study, the athletes on a long-term KD depleted muscle glycogen at the same rate as the “high-carb” athletes during a 3-hour submaximal run, which suggests that their metabolic machinery to perform glycolysis was still present. However, if PDH activity had been measured, it is likely to have been lower in the KD group. In those athletes, pyruvate will not be metabolized by PDH, but instead be diverted by pyruvate carboxylase (PC) to make oxaloacetate for anapleurosis (replenishing Krebs cycle intermediates that have been diverted to other metabolic pathways). This oxaloacetate is required within the Krebs cycle to accept acetyl-CoA coming from other fuels (i.e., fatty acids or ketone bodies). In agreement with this, recent work suggests that coadministration of glucose as an anapleurotic substrate maximizes the benefit from exogenous ketones (2).

In “keto-adapted” athletes, the ability to oxidize fat at higher intensities will mean that, at a given exercise intensity, they will require less PDH activity and more PC activity. If PDH activity is then used as the main metric of whether a low-carb diet affects the capacity to perform glycolysis, it will give a biased view. Perhaps it is not that glycolysis is suppressed, just that the end product of glycolysis (pyruvate) is used differently after fat adaptation. In this scenario, carbohydrate availability (for anapleurosis) could still be rate limiting in athletes on a KD during prolonged aerobic work (8).

In contrast, if decreased PDH activity while on a KD is indeed a detrimental loss of metabolic machinery, then there is a possibility that glycolytic training could mitigate this effect, as substrate utilization during exercise is at least partially driven by demand (i.e., aerobic versus anaerobic exercise). After high-intensity glycolytic “sprint” training, PDH activity increases (1,3). Therefore, although sprint performance can quantitatively drop during acute carbohydrate restriction (because of reduced substrate availability), maintaining higher intensity glycolytic training during periods of carbohydrate restriction could help to maintain PDH activity. This will likely require a more intense training effort and longer adaptation period than has been examined previously (7), but may enable an athlete to remain metabolically “flexible” during carbohydrate restriction, maximizing their capacity to use carbohydrates when they are reintroduced to the diet.


1. Burgomaster KA, Heigenhauser GJ, Gibala MJ. Effect of short-term sprint interval training on human skeletal muscle carbohydrate metabolism during exercise and time-trial performance. J Ap Phys (1985) 100: 2041–2047, 2006.
2. Cox PJ, Kirk T, Ashmore T, Willerton K, Evans R, Smith A, Murray AJ, Stubbs B, West J, McLure SW, King MT, Dodd MS, Holloway C, Neubauer S, Drawer S, Veech RL, Griffin JL, Clarke K. Nutritional ketosis alters fuel preference and thereby endurance performance in athletes. Cell Metab 24: 256–268, 2016.
3. Howlett RA, Heigenhauser GJ, Spriet LL. Skeletal muscle metabolism during high-intensity sprint exercise is unaffected by dichloroacetate or acetate infusion. J Ap Phys (1985) 87: 1747–1751, 1999.
4. Impey SG, Hammond KM, Shepherd SO, Sharples AP, Stewart C, Limb M, Smith K, Philp A, Jeromson S, Hamilton DL, Close GL, Morton JP. Fuel for the work required: A practical approach to amalgamating train-low paradigms for endurance athletes. Phys Repor 4, 2016.
5. Kavalek M, Gannon R, Nelson MT. A case for and against ketogenic diets in athletes. Strength Cond J 39: 27–31, 2017.
6. Marquet LA, Brisswalter J, Louis J, Tiollier E, Burke LM, Hawley JA, Hausswirth C. Enhanced endurance performance by periodization of carbohydrate intake: “Sleep low”. Strategy Med Sci Sp Exerc 48: 663–672, 2016.
7. Stellingwerff T, Spriet LL, Watt MJ, Kimber NE, Hargreaves M, Hawley JA, Burke LM. Decreased PDH activation and glycogenolysis during exercise following fat adaptation with carbohydrate restoration. Am J Phys Endocrin Metab 290: E380–E388, 2006.
8. Volek JS, Freidenreich DJ, Saenz C, Kunces LJ, Creighton BC, Bartley JM, Davitt PM, Munoz CX, Anderson JM, Maresh CM, Lee EC, Schuenke MD, Aerni G, Kraemer WJ, Phinney SD. Metabolic characteristics of keto-adapted ultra-endurance runners. Metab Clin Experim 65: 100–110, 2016.
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