10.1146@annurev Nutr 082018 124337

NU39CH10_Kiens ARjats.
cls May 20, 2019 13:23
Annual Review of Nutrition

Dietary Fuels in Athletic
Performance
Andreas Mæchel Fritzen, Anne-Marie Lundsgaard,
and Bente Kiens
Section of Molecular Physiology, Department of Nutrition, Exercise and Sports,
Annu. Rev. Nutr. 2019.39. Downloaded from www.annualreviews.org
Access provided by 5.62.159.49 on 07/21/19. For personal use only.
Faculty of Science, University of Copenhagen, Copenhagen 2200, Denmark;

email: amfritzen@nexs.ku.dk, amlundsgaard@nexs.ku.dk, bkiens@nexs.ku.dk
Annu. Rev. Nutr. 2019. 39:10.1–10.29 Keywords

The Annual Review of Nutrition is online at
exercise, training, nutrition, carbohydrate, fat, protein
nutr.annualreviews.org
https://doi.org/10.1146/annurev-nutr-082018- Abstract
124337
Focusing on daily nutrition is important for athletes to perform and adapt
Copyright © 2019 by Annual Reviews.
optimally to exercise training. The major roles of an athlete’s daily diet
All rights reserved
are to supply the substrates needed to cover the energy demands for ex-
ercise, to ensure quick recovery between exercise bouts, to optimize adapta-
tions to exercise training, and to stay healthy. The major energy substrates
for exercising skeletal muscles are carbohydrate and fat stores. Optimizing
the timing and type of energy intake and the amount of dietary macronutri-
ents is essential to ensure peak training and competition performance, and
these strategies play important roles in modulating skeletal muscle adapta-
tions to endurance and resistance training. In this review, recent advances in
nutritional strategies designed to optimize exercise-induced adaptations in
skeletal muscle are discussed, with an emphasis on mechanistic approaches,
by describing the physiological mechanisms that provide the basis for dif-
ferent nutrition regimens.
10.1
Review in Advance first posted on
May 28, 2019. (Changes may still
occur before final publication.)
NU39CH10_Kiens ARjats.cls May 20, 2019 13:23
Contents
1. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.2
2. DAILY CARBOHYDRATE INTAKE FOR ATHLETES: REQUIREMENTS
FOR OPTIMAL RECOVERY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.3
2.1. The Role of Carbohydrates During Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.3
2.2. Mechanisms Favoring Glycogen Replenishment After Exercise . . . . . . . . . . . . . 10.3
2.3. Carbohydrate Intake and the Limit for Glycogen Synthesis in Muscle . . . . . . . 10.4
2.4. Limitations on the Muscle Glycogen Synthesis Rate . . . . . . . . . . . . . . . . . . . . . . . . 10.5
2.5. The Glycemic and Insulinemic Potential of Carbohydrates . . . . . . . . . . . . . . . . . 10.5
2.6. Fructose in the Post-Exercise Diet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.6
2.7. The Daily Window for Carbohydrate Intake . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.6
2.8. The Importance of Restoring Glycogen Content Before Exercise . . . . . . . . . . . 10.7
3. DIETARY FAT FOR ATHLETES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.8
3.1. Adaptions to Exercise Training and a High-Fat Diet . . . . . . . . . . . . . . . . . . . . . . . . 10.8
3.2. Exercise Performance After Increased Ingestion of Dietary Fat . . . . . . . . . . . . . . 10.9

3.3. Mechanisms Underlying Impaired Endurance Performance
After Consumption of a High-Fat Diet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.10
3.4. Ketogenic Aids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.11
4. DIETARY PROTEINS FOR ATHLETES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.13
4.1. Resistance Exercise: Role of Dietary Protein for Strength
and Muscle Hypertrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.13
4.2. Endurance Exercise: Role of Dietary Protein in Performance
and Training Adaptions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.16
4.3. Timing of Dietary Protein Intake for Adaptations Due
to Resistance Training . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.17
4.4. Sources and Types of Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.18
1. INTRODUCTION
Athletes undertake an exceptional amount of training, which is why focusing on their daily diet is
of great importance. The major roles of an athlete’s daily diet are to supply the nutrients needed to
cover the energy demands of their training program, to optimize the adaptations achieved during
and in response to training sessions, and to ensure quick recovery between workouts. Also, athletes
must eat to stay in good health and avoid dietary practices that might compromise health. Evidence
demonstrates that dietary macronutrient availability is essential for optimal performance and plays
an important role in modulating skeletal muscle adaptations to endurance and resistance training.
This review highlights recent advances in our understanding of nutritional strategies that opti-
mize exercise-induced adaptations in skeletal muscle. An important aim of this review is to take
a mechanistic approach, by describing the molecular and physiological mechanisms that underlie
different nutrition regimens.
The primary energy fuels for exercise are glucose and fatty acids (FAs). Exercise intensity and
duration are important regulators of the relative extent to which glucose and FAs act as fuels during
aerobic exercise. When aerobic exercise intensity increases from moderate to higher intensities,
a gradual shift occurs from the dual oxidation of glucose and FAs to primarily glucose oxidation
(91). Under conditions of prolonged exercise at low-to-moderate intensities, there is a gradual
10.2 Fritzen • Lundsgaard • Kiens

increase in FA utilization at the expense of carbohydrates as fuel, which occurs concurrently with
decreased glucose availability (91). Therefore, during prolonged or high-intensity exercise, the
utilization of endogenous dietary carbohydrates stores is great.
2. DAILY CARBOHYDRATE INTAKE FOR ATHLETES: REQUIREMENTS

FOR OPTIMAL RECOVERY
2.1. The Role of Carbohydrates During Exercise
The main fuel utilized during heavy exercise is carbohydrates. Glycogen stored within the mus-
cles and plasma glucose released from the liver provide the carbohydrate sources for muscle
energy requirements. During prolonged exercise without carbohydrate supplementation and in
high-intensity exercise, a depletion of both muscle and liver glycogen may occur: The rate of
glycogenolysis in muscle (45) and liver (109) is reported to increase in linearly with exercise in-
tensity. Due to the limited amount of endogenous carbohydrate sources, the depletion of mus-
cle glycogen stores during prolonged constant or intermittent exercise appears within approx-
imately 70–120 min at approximately 70–80% of maximal oxygen consumption (VO2max ) (69,
79). Even 3.5 min of high-intensity cycling has been shown to reduce muscle glycogen by 25%
(149).
In addition to the increased mobilization of hepatic glycogen, plasma glucose availability is also
met by hepatic gluconeogenesis during exercise. Hepatic glycogenolysis comprises 50–70% and
gluconeogenesis comprises 30–50% of hepatic glucose output during exercise at 72% of VO2max
(151). Liver glycogen has been reported to be 60% depleted within 90 min of exercise at 70% of
VO2max (29). Accordingly, nutritional strategies have focused on establishing carbohydrate avail-
ability that enables adequate replenishment of carbohydrate stores before the next exercise session.
2.2. Mechanisms Favoring Glycogen Replenishment After Exercise

For the athlete exercising daily or twice a day, a high glycogen resynthesis rate is important to re-
plenishing glycogen stores. To maximize carbohydrate resynthesis, carbohydrate intake in the first
hours following exercise is important. Thus, the exercise-induced translocation of glucose trans-
porter 4 (GLUT4) protein from vesicles located in the cytosol to the plasma membrane and the
increased activity of muscle glycogen synthase [which increases linearly with the degree of glyco-
gen depletion (164)] set the stage for increased plasma glucose uptake in the early post-exercise
period. The exercise-induced increase in muscle glucose uptake reverses within 2–4 h, and, there-
fore, glycogen resynthesis following exercise is low as long as there is no carbohydrate ingestion.
However, the insulin sensitivity of the muscles engaged in exercise is increased for many hours
following exercise, so when carbohydrates are consumed, this leads to a greater ability of insulin
to increase microvascular perfusion (126) and, hence, to deliver glucose and insulin to the mus-
cles. Furthermore, the increased insulin sensitivity also results in further GLUT4 translocation
to the plasma membrane (52) and activation of glycogen synthase (159). Together, these physio-
logical changes support increased peripheral glucose disposal into skeletal muscle glycogen upon
carbohydrate intake following exercise (105).
The importance of ingesting carbohydrates soon after the termination of exercise to maximize
glycogen resynthesis has been shown in several studies. Thus, whole-body glucose disappearance
has been shown to be greater than 40% when a mixed meal was given immediately after exercise as
compared with a meal consumed 3 h later (89). It has also been shown that ingesting a carbohydrate
solution 3 h after exercise as compared with immediately after resulted in a 26% lower muscle
www.annualreviews.org • Dietary Fuels in Athletic Performance 10.3

glycogen synthesis rate at 4 h post-exercise (69), while a 2 h delay in intake of a carbohydrate-

rich meal had no effect when glycogen content was evaluated at 8 h post-exercise (107). Together,
these data point to the need to prioritize the intake of carbohydrates within the hours immediately
following exercise, when it is necessary to maximize glycogen synthesis and also take advantage of
the optimized molecular machinery for muscle glycogen storage. An important consideration is
that failing to consume carbohydrates in the early recovery phase post-exercise leads to low rates
of glycogen restoration until carbohydrate intake occurs (69).
2.3. Carbohydrate Intake and the Limit for Glycogen Synthesis in Muscle
Data from 25 studies assessing muscle glycogen resynthesis rates within the hours immediately
following prolonged glycogen-depleting exercise indicate that in response to carbohydrate intakes
of 0–2.1 g/kg per h, the highest muscle glycogen resynthesis rate achieved in trained participants
(VO2max = 56–67 ml/kg per min) was 11–12 mmol/kg ww per h (kilogram of wet weight per
hour) within 6 h post-exercise (Figure 1). Importantly, no additional benefit to muscle glycogen
resynthesis rate seems to occur with carbohydrate intakes beyond 1–1.2 g/kg per h. In 20 of 25
studies, carbohydrates were ingested as glucose beverages, but no obvious differences in synthesis
rates were observed between liquid or solid carbohydrate sources, which is congruent with findings
that directly compared this (119). Interestingly, greater glycogen resynthesis rates in response to
the same carbohydrate intake were obtained in trained individuals (11–12 mmol/kg ww per h)
15
Glycogen synthesis rate
10
(mmol/kg ww per h)
Trained
Untrained to
moderately trained
5
0 0.5 1.0 1.5 2.0 2.5

Carbohydrate intake (g/kg per h)
Figure 1
Scatter plot illustrating the association between carbohydrate intake and muscle glycogen resynthesis rates
measured up to 6 h after exhaustive glycogen-depleting exercise that reduced glycogen to 13–36 mmol/kg
ww (wet weight) per h. Trained and untrained-to-moderately trained participants were defined using the
categories VO2max >55 ml/kg per min or ≤55 ml/kg per min, respectively. The carbohydrate provided in
the studies comprised mostly liquids in the form of glucose, glucose polymers, and sucrose in various
concentrations (20 studies), but 5 studies used solid, carbohydrate-rich foods. In the figure, and for the
studies cited in the text, a factor of 4.28 was used to convert glycogen content in mmol/kg dry weight to
mmol/kg ww. Data from the following studies are included in the figure: 1, 13, 14, 28, 30, 39, 62, 66, 68–70,
73, 74, 97, 113, 119, 142, 143, 145, 147, 150, 155, 160, 163–165.

compared with participants who were only active recreationally or who trained only moderately
(VO2max ≤ 55 ml/kg per min; 5–6 mmol/kg ww per h) (Figure 1).
2.4. Limitations on the Muscle Glycogen Synthesis Rate

Muscle glycogen synthesis is limited by a combination of factors. From glucose infusion studies,
it appears that muscle glycogen synthesis rates of 11–12 mmol/kg ww per h are not maximal.
Hence, with intravenous infusion of glucose at doses of 1 g/kg per h, 4 h post-exercise muscle
glycogen resynthesis rates of ∼20 mmol/kg ww per h have been reported in untrained participants
(11), while a constant co-infusion of glucose and insulin during a hyperinsulinemic–hyperglycemic
clamp resulted in glycogen resynthesis rates of 44 and 32 mmol/kg ww per h at 2 h and 4 h of
recovery, respectively, in moderately trained participants (51). The up to fourfold greater muscle
glycogen synthesis rates obtained when both hyperglycemia and hyperinsulinemia were achieved
compared with the values obtained under normal conditions with carbohydrate intake, indicate
that circulating insulin levels, intestinal absorption, and the efficiency of the splanchnic bed in
making oral glucose available for systemic circulation are important for muscle glycogen storage.
When the absorption step has been investigated in resting individuals by providing a
carbohydrate-rich meal (∼100 g of carbohydrate) and using three different glucose tracers, the
peak rate of glucose appearance in systemic circulation was estimated to be ∼1.2 g/kg per h (9),
which also seems to be similar to the level of carbohydrate intake at which muscle glycogen resyn-
thesis levels off post-exercise (Figure 1). Interestingly, it has been shown that glucose appears in
systemic circulation to a 30–50% greater extent following a meal during recovery from exercise
when compared with after rest (95, 122). At the same time, prior exercise substantially increases
hepatic extraction of glucose in the portal vein and its synthesis of glycogen compared with a prior
resting situation (108).
The finding that trained participants obtain ∼100% greater muscle glycogen resynthesis rates
during early recovery compared with untrained participants (Figure 1) can be ascribed to training-
induced adaptations in skeletal muscle, such as increased capillary density and increased content
of the glucose metabolic protein machinery, including GLUT4, hexokinase 2 (HK2), insulin re-
ceptor, Akt, Akt substrate of 160 kDa (AS160), and glycogen synthase, all of which have been
coupled with training-induced increases in insulin sensitivity (43). Collectively, these adaptations
contribute to the greater sensitivity for muscle glycogen synthesis in response to a given level
of circulating insulin and glucose. Thus, whereas gut absorption might limit the total amount of
glucose that can be taken up into the circulation (∼1.2 g/kg per h), local vasculature and glu-
cose metabolic properties of the exercised muscle are important for glucose uptake and glycogen
synthesis in the muscle. It should be noted that along with the higher muscle resynthesis rates,
muscle glycogen content generally is also greater in individuals who have been endurance trained
compared with those who are untrained, with typical content of ∼120 and ∼90 mmol/kg ww,
respectively (10).
2.5. The Glycemic and Insulinemic Potential of Carbohydrates

The glycemic index (GI) of carbohydrates refers to the effect of a given carbohydrate dose on post-
prandial blood glucose concentrations. The effect of high, moderate, or low GI carbohydrates on
muscle glycogen synthesis has mainly been investigated during prolonged recovery periods. In one
study in junior elite cyclists, a greater 24-h muscle glycogen content was observed after consump-
tion of a carbohydrate-rich diet (10 g/kg) with a high GI compared with a diet with a moderate
GI (23). In well-trained males, in the first 6 h after glycogen-depleting exercise, muscle glycogen

resynthesis rates of ∼8 mmol/kg ww per h and ∼5 mmol/kg ww per h were reported following
the consumption of carbohydrate-rich meals [65–70 energy % (E%)] with high and low GIs, re-
spectively (78; B. Kiens, unpublished observations). When consuming frequent carbohydrate-rich
meals (65–70 E%) of moderate-to-high GI foods, muscle glycogen stores were replenished after
22–24 h (79), whereas ∼40 h were needed when a carbohydrate-rich diet with low GI foods was
ingested (B. Kiens, unpublished observations).
Taken together, these findings show that the type of dietary carbohydrate consumed is impor-
tant for the rate of glycogen restoration. Importantly, eating frequent meals of high-to-moderate
GI foods, which maintains elevations in plasma glucose and insulin, is beneficial for maximizing
glycogen storage.
2.6. Fructose in the Post-Exercise Diet

In the diet in general, and especially in post-exercise meals for many athletes, most carbohydrate
sources contain fructose together with glucose, and fructose is also provided in the majority of
energy drinks and gels habitually ingested by many athletes. The fructose content of foods influ-
ences the level of plasma insulin and glucose. After ingestion of a fructose load, plasma glucose and
fructose levels show little change. This is because a large amount of ingested fructose in the portal
vein is extracted at first-pass in the liver and metabolized. Accordingly, fructose has only minimal
effect on concentrations of circulating glucose and insulin when compared with glucose ingestion
(36) and, therefore, it appears to be a poor nutritional precursor for muscle glycogen synthesis.
Muscle glycogen synthesis is compromised when fructose or sucrose is ingested compared with the
ingestion of isoenergetic glucose alone at matched intakes of ∼0.7 g/kg per h following exercise
(14). This compromise is coupled with lower plasma insulin responses compared with ingestion
of glucose. However, when a solution of 1.2 g/kg per h was ingested as either glucose or glucose
and fructose (in a ratio of 2:1), muscle glycogen resynthesis was similar during early recovery (4 h
post-exercise) under conditions of similar plasma insulin and glucose concentrations (150). From
this, it appears that the presence of fructose in dietary carbohydrate sources does not compromise
muscle glycogen synthesis when sufficient total carbohydrate intake is assured.
In the liver, fructose can be converted into glucose or lactate, thereby providing a substrate for
hepatic glycogen synthesis. It has been documented by 13 C magnetic resonance spectroscopy that
co-ingestion of glucose and fructose seems to double liver glycogen resynthesis after exhaustive
exercise compared with ingestion of isoenergetic glucose (47). Therefore, glucose plus fructose in-
take seems to induce efficient hepatic glycogen synthesis. This could be important for endurance
athletes who may benefit from ingesting carbohydrates containing both monosaccharides follow-
ing an overnight fast, after which liver glycogen content is found to be reduced by ∼30–35%
(123).
2.7. The Daily Window for Carbohydrate Intake

With the depletion of 90–100 mmol/kg ww after prolonged exercise and a maximal glycogen syn-
thesis rate of 11–12 mmol/kg ww per h, the depleted glycogen may theoretically be replenished
within ∼10 h of recovery. However, it appears that 20–24 h or more may be necessary for full
glycogen replenishment to occur under optimal dietary conditions (79), likely due to the facts
that (a) glucose and insulin are not at optimal concentrations during the whole resynthesis period;
(b) glycogen synthesis rates decrease over time as stores are gradually replenished (164); (c) el-
ements of eccentric training during exercise may impair the glycogen synthesis rate as a result
of reduced muscle glucose uptake (6); (d) habitual daily physical activity also affects glycogen

replenishment; (e) usually a mixture of macronutrients will be ingested during the day, which also
influences the glycemic load of meals; and ( f ) at night, the glycogen synthesis rate is low.
Regarding the total amount of carbohydrates needed daily to fully replenish glycogen stores,
several studies have shown that there is a direct and positive relationship between the quantity
of dietary carbohydrate ingested and post-exercise glycogen storage within 24 h until the muscle
storage capacity, or threshold, reaches a total daily dietary carbohydrate intake of 7–10 g/kg per
day. Carbohydrate intake beyond that threshold appears not to enhance glycogen storage further
(24). For athletes with a high number of weekly training sessions or two training sessions daily,
or both, an amount of dietary carbohydrates in this range may be necessary to ensure optimal
glycogen stores at every training session. It is worth noting that ingestion of such substantial
amounts of carbohydrate might affect the ability to include other important dietary constituents
and sufficient amounts of total energy (65). To this end, lower total intakes of carbohydrates may
be sufficient for the athlete involved in training programs that do not lead to daily depletion
of glycogen content. Guidelines for total carbohydrate intake for athletes with various training
schedules have recently been reviewed (139).
Achieving high carbohydrate availability entails some practical issues for the athlete as the
number of postprandial hours available to the athlete represents a limitation to daily intake. Ac-
cordingly, many athletes commence training sessions with some degree of depletion of muscle
glycogen stores, especially if exercising twice daily.
2.8. The Importance of Restoring Glycogen Content Before Exercise

What then is the effect of exercising with low glycogen in relation to molecular adaptations
in muscle to endurance training, and what is the effect on performance? The hormonal and
metabolic responses during exercise with low whole-body glycogen availability typically include
lower plasma concentrations of glucose and lactate, greater plasma catecholamine concentrations
and FA levels (158), lower insulin levels (117), and increased concentration of the ketone body β-
hydroxybutyrate (B-OH) (67). Hence, whole-body FA oxidation is greater in those exercising with
low glycogen stores than in a control group commencing exercise with normal muscle glycogen
content (158).
Exercise undertaken with low initial muscle glycogen levels has been shown to result in greater
activation of energy stress pathways, such as adenosine monophosphate-activated protein kinase
(AMPK) signaling (129, 158), and enhanced transcriptional responses in traditional exercise-
regulated genes, such as peroxisome proliferator–activated receptor gamma coactivator 1 alpha
(PGC1A) (117), GLUT4 (129), HK2, pyruvate dehydrogenase kinase 4 (PDK4) (114), cytochrome
C oxidase 1 (COX1) (117), mitochondrial uncoupling protein 3 (UCP3), and lipoprotein lipase
(LPL) (114).
Accordingly, when exercise training for 3 weeks consisted of daily exercise plus two exercise
bouts every second day, during which the second bout was consequently performed with low glyco-
gen stores (low training), greater increases in maximal β-hydroxyacyl-coenzyme A (CoA) dehy-
drogenase (HAD) and citrate synthase (CS) activity in both untrained and trained participants (50,
162) and greater maximal COX4 (162) and HAD protein content (67) were found compared with
training performed every day with glycogen stores replenished before exercise. One study also
showed that low training increased the capacity for FA uptake and mitochondrial FA utilization,
as fatty acid binding protein (FABP) and UCP3 protein contents were increased (38).
Collectively, these studies suggest that exercising with reduced muscle glycogen, which oc-
curs when full replenishment after prior exercise is not achieved, does not compromise exercise-
induced metabolic adaptations and may be an even more potent stimulus to induce metabolic

adaptations. However, it appears that low glycogen availability before exercise inhibits the abil-
ity to sustain high exercise intensity (162), which is known to be crucial to making adaptations
to exercise training. So despite the observations that the reduction in power output during low
training sessions did not translate into impaired exercise performance after 3 weeks of training
(67, 162), it may be that longer periods with many of these training sessions leads to impaired
performance. Therefore, competitive athletes should prioritize ingestion of dietary carbohydrates
to ensure pre-exercise replenishment of glycogen stores to allow for high-intensity training.
3. DIETARY FAT FOR ATHLETES

As discussed above, dietary carbohydrate availability appears to be important to meet the demands
of daily endurance training that includes high-intensity exercise and volume. However, an alterna-
tive to the optimal substrate support for endurance exercise could be to maximize the contribution
of dietary fat as a substrate for exercising muscle through daily consumption of a diet high in fat
(≥60 E%) and low in carbohydrates (<25 E%), with a moderate intake of proteins (∼15 E%).
For years, it has been debated whether exposure to such a high-fat diet while undertaking daily
exercise training could amplify training-induced adaptations and, thereby, increase the capacity
for FA and ketone body oxidation, reduce carbohydrate utilization, and, hence, delay the onset of
fatigue during prolonged exercise, and, consequently, improve performance.
3.1. Adaptions to Exercise Training and a High-Fat Diet

When consuming a diet high in fat and low in carbohydrates, a major metabolic shift toward
higher FA oxidation occurs. This is clearly demonstrated in individuals who have fasted overnight,
in whom the resting whole-body respiratory exchange ratio decreases markedly on a high-fat diet
(to 0.75) compared with the ratio on a mixed diet (0.82) (92). The increased FA availability with
high-fat diets induces several adaptations in skeletal muscle. In a well-controlled laboratory study
conducted in healthy, sedentary men consuming a high-fat (65 E%), low-carbohydrate (20 E%)
diet for 6 weeks, increases were obtained in protein levels in skeletal muscle of the lipid trans-
porter cluster of differentiation 36/scavenger receptor class B protein type 2 (CD36), and fatty acid
transport protein 1 (FATP1) and 4 (FATP4) (92). These adaptations allow an increased capacity
for transmembrane uptake and handling of plasma FAs in skeletal muscle. In addition, the mito-
chondrial capacity adjusts to increased FA oxidation as the activity of HAD is increased, whereas
pyruvate dehydrogenase complex (PDC) activity, and thereby the capacity for PDC-mediated
conversion of pyruvate to acetyl-CoA, decreases. This permits greater β-oxidation and uptake of
β-oxidation-derived acetyl-CoA into the tricarboxylic acid (TCA) cycle (56, 92). Hence, a high-fat
diet per se induces several molecular adaptations in skeletal muscle that contribute to an increased
capacity for FA uptake and oxidation. Several of these adaptations are already evident in healthy
volunteers after 3 days on a high-fat diet providing energy excess (93).
The question is whether exercise training combined with a high-fat diet will stimulate mus-
cle metabolic adaptations additively. In humans, the number of proteins known to be changed in
skeletal muscle by endurance training in combination with a high-fat diet is limited. In mice,
however, a proteomic analysis of the gastrocnemius muscle from mice fed a high-fat diet for
20 weeks identified 56 proteins, primarily related to FA metabolic pathways, that were altered
compared with those in control mice fed a low-fat diet (84). When mice were fed a high-fat diet
while exercise-trained for 20 weeks, 29 proteins were altered compared with sedentary nontrained
control mice fed a high-fat diet; all of the altered proteins were related to FA metabolism. Notably,
there was considerable overlap between the proteins regulated by the high-fat diet and by exercise

training, as exercise training altered 26 of the 56 proteins in the same direction as those altered
by the high-fat diet (84). These findings demonstrate that the consumption of a high-fat diet in-
creases FA metabolic capacity in a similar direction to exercise training. Interestingly, despite the
FA metabolic adaptations elicited by the high-fat diet, the mice did not improve their running
capacity.
One of the longest studies in humans examining high-fat diets and exercise training was con-
ducted in untrained volunteers following an aerobic endurance training program undertaken while
consuming either a high-fat (62 E%) or a high-carbohydrate (65 E%) diet for 7 weeks (56). At the
end of the training period, muscle HAD activity was increased by ∼25% for those on the high-
fat diet, but it remained unchanged for those on the carbohydrate-rich diet. However, the maxi-
mal activity of both HK2and CS increased with exercise training on both the high-fat and high-
carbohydrate diets (56). Thus, in agreement with the study in mice, training while on a high-fat
diet induced increased lipid oxidation capacity compared with training while on a carbohydrate-
rich diet. Only few studies have been undertaken in trained individuals to assess the effects of a
high-fat diet on metabolic proteins in skeletal muscle. When endurance-trained cyclists or triath-
letes consumed a high-fat (>65 E%), low-carbohydrate (<20 E%) diet for 5–6 days while main-
taining their habitual training schedule, no changes were observed in the abundance in muscles
of GLUT4 and PGC-1α (161), the levels of proteins in the oxidative phosphorylation pathway,
or the activity of CS (86) and HAD (44) compared with when the same participants remained
on a carbohydrate-rich diet. Also, the abundance of CD36 remained unchanged in one study
(161), whereas in another study, CD36 protein abundance and messenger RNA expression were
increased after 5 days on a high-fat diet compared with an isoenergetic carbohydrate-rich diet
(70–75 E%) (27).
Taking these findings together, it appears that diets high in fat upregulate the enzymatic ma-
chinery in skeletal muscle toward enhanced FA metabolism, permitting enhanced FA oxidation.
However, in endurance-trained individuals in whom such adaptations already exist, further adap-
tations to a high-fat diet appear to be limited, and this is why there seems to be little theoretical
basis for the idea that additional performance benefits will be gained from consuming a high-fat
diet in those individuals.
3.2. Exercise Performance After Increased Ingestion of Dietary Fat

The question is, therefore, whether these adaptations to increased fat consumption bring
about improved physical performance. Studies in trained individuals consuming high-fat, low-
carbohydrate diets for periods lasting from 1 to 5 weeks revealed an expected increase in whole-
body FA oxidation during submaximal exercise compared with when a carbohydrate-rich diet is
consumed for the same duration (reviewed by Burke in Reference 21). However, most of these
short-term studies revealed no performance advantages from a high-fat, low-carbohydrate diet
relative to a carbohydrate-rich diet. In a recent study, elite race walkers were followed during 3
weeks of intensified training while consuming either a ketogenic high-fat (78 E%), carbohydrate-
restricted (<50g/day) diet or a carbohydrate-rich diet (8.6 g/kg per day) (25). After 3 weeks, VO2max
was increased to a similar extent after both dietary interventions. Despite the increase in VO2max
and markedly higher FA oxidation during two intense performance tests (of 10 and 20 km) af-
ter adaptation to the ketogenic high-fat diet, this dietary regimen did not lead to improved per-
formance, which was ascribed to FA-induced impairment in exercise economy (25). In contrast,
training with the carbohydrate-rich diet was associated with improved race outcomes (25).
In a longer-term study (7 weeks), healthy, relatively untrained men consumed a high-
fat (62 E%), low-carbohydrate (22 E%) diet while engaging in a training intervention (57).

Compared with before the intervention, consumption of the high-fat diet resulted in a marked
increase in FA oxidation, both at rest and during a performance test. Despite the fact that FA
oxidation was higher during exercise in the group eating a high-fat diet, training-induced im-
provement in performance, measured on a bicycle as the time to exhaustion at 70% of VO2max ,
was much less (65 min) than in a matched group of men who consumed a high-carbohydrate
(66 E%), low-fat (19 E%) diet while following the same training protocol (102 min) (57).
When exercise performance was measured as time to exhaustion after 2 and 4 weeks of exercise
training in these initially untrained individuals on the high-fat or high-carbohydrate diet, a sim-
ilar training-induced increase in performance was obtained in both groups. But beyond 4 weeks,
despite continuing training and following their respective diet protocols, time to exhaustion did
not increase further in the group eating the high-fat diet, while an additional increase of 29%
was achieved in the group consuming the carbohydrate-rich diet (60, 78). These findings indi-
cate that when commencing exercise training, the exercise stimuli appear to be superior to diet
in improving endurance performance. But beyond 4 weeks, nutrient signaling plays an important
role in performance, and it seems that a carbohydrate-rich diet is superior to the outcomes pro-
duced by a high-fat diet. Most studies in athletes consuming a high-fat diet have been conducted
for 4 weeks or fewer, which may be why endurance performance capacity in some studies was
maintained during moderate-to-high-intensity exercise. However, a diminished improvement in
exercise performance in athletes on a longer-term high-fat diet relative to a carbohydrate-rich diet
cannot be excluded and is actually something we would predict.
Several studies have evaluated the effects of shorter-term adaptations (5–7 days) to a high-fat
diet (>60 E%) followed by carbohydrate loading for 1 day, which has been suggested as a strategy
to acutely improve performance before competition. The underlying idea is that in addition to the
FA-induced adaptations toward enhanced FA oxidation capacity, lowering the glycogen stores, as a
consequence of low carbohydrate intake, will enable increased (that is, supercompensate) glycogen
stores when switching to subsequent carbohydrate loading. Theoretically, such a strategy could
favor high FA oxidation during endurance exercise and save glycogen for a final sprint or to delay
fatigue.
From these studies it appears that despite achieving an increase in the capacity to oxidize
FAs during submaximal exercise after short-term exposure to a high-fat diet combined with the
restoration of muscle glycogen stores, performance was not improved compared with consump-
tion of a high-carbohydrate diet (22). When a series of sprints were undertaken during a 100-km
trial in well-trained cyclists at high power output (>90% of peak power output), performance
was reduced after consuming a high-fat diet followed by a carbohydrate-rich diet (55). Together,
these findings show that these kinds of pre-event strategies are not superior to consumption of a
carbohydrate-rich diet.
3.3. Mechanisms Underlying Impaired Endurance Performance

After Consumption of a High-Fat Diet
Impaired endurance performance after a high-fat diet can be explained by an impaired ability
to oxidize carbohydrates during exercise. In a study by Helge et al. (58), substrate kinetics and
metabolism were investigated during 60 min of exercise performed at 68% of VO2max on a bi-
cycle ergometer after 7 weeks of exercise training with concomitant ingestion of either a high-
fat or carbohydrate-rich diet. During exercise, the respiratory quotient measured across the leg
demonstrated higher FA oxidation after consumption of the high-fat diet than after the high-
carbohydrate diet. Plasma glucose uptake measured across the leg was similar in the two trials,
although arterial plasma glucose concentration was higher during exercise in the high-fat trial

than in the carbohydrate-rich trial, suggesting that FAs induced inhibition of muscle glucose up-
take. At the same time, muscle glycogen break down was lower in the high-fat trial (0.61 mmol/kg
ww per min) than in the high-carbohydrate trial (1.12 mmol/kg ww per min). Interestingly, when
carbohydrate availability was subsequently enhanced by 1 week of carbohydrate loading following
the 7 weeks on the high-fat diet (combined with continuing the exercise training) (HFHCHO),
supercompensated muscle glycogen stores were obtained (204 ± 14 mmol/kg ww), but this did not
lead to higher glycogen utilization during exercise than when an isoenergetic carbohydrate-rich
(65 E%) diet was consumed during all 8 weeks (161 ± 10 mmol/kg ww) (HCHO). In addition,
glucose uptake in the exercising leg was lower in the prior fat-adapted trial (HFHCHO) despite
higher glucose availability in plasma compared with when carbohydrates were ingested through-
out the 8 weeks (HCHO) (59). These studies strongly indicate that adaptation to high-fat diets
impairs the utilization of carbohydrates rather than sparing carbohydrates as an energy source
during exercise. Translating this into performance, in the high-fat trial, performance was ∼30%
lower even after carbohydrate loading compared with consumption of the carbohydrate-rich diet
throughout the 8 weeks (57). Impaired glycogenolysis and downregulation of muscle glucose up-
take under conditions of high dietary FA availability may be explained by impaired metabolic
flexibility, in which PDK4 is considered a key regulator. FA-induced increases in PDK4 promote
FA oxidation by decreasing PDC activity, thereby enhancing the entry of β-oxidation-derived
acetyl-CoA into the TCA cycle and inhibiting the conversion of pyruvate into acetyl-CoA. Levels
of PDK4 protein are increased after consumption of a high-fat diet in both humans (93) and mice
(84), leading to a sustained decrease in PDC activity (93, 130), which is likely the reason for the in-
hibition of carbohydrate oxidation and decreased performance. In contrast, when a carbohydrate-
rich diet is consumed, increased PDC activity enables the entry of pyruvate-derived acetyl-CoA
for the TCA cycle (93, 130).
In summary, the data appear to show that steady-state exercise at low-to-moderate intensity can
be maintained after adaptation to a ketogenic or nonketogenic high-fat diet (21, 99), at least on a
short-term basis. However, it is evident that at the higher intensities relevant for many endurance
athletes, a diet high in fat is inferior to a diet high in carbohydrate in improving performance in
response to a training intervention.
That being said, dietary fat is also an important nutrient. Including fat in the diet, in addition
to providing essential FAs and fat-soluble vitamins, may help to meet the total energy demand,
especially in athletes with high energy expenditures. This is due to the lower energy density in
low-fat diets and is supported by findings showing that when a diet comprises moderate-to-high
rather than low-fat content in a free-living ad libitum setting, in endurance runners, energy intake
is closer to meeting energy expenditure than when they are consuming a low-fat diet (65).
3.4. Ketogenic Aids

The idea behind a ketogenic diet is that in addition to increasing FA oxidation, it raises the blood
level of ketone bodies so that they serve as an alternative and more efficient fuel source and,
thereby, benefit performance during endurance exercise. To avoid the limitations and side effects
from exposure to a ketogenic diet, an alternative method of raising blood concentrations of ketones
is the oral ingestion of ketone body supplements.
The primary tissues responsible for the uptake and oxidation of circulating ketones (B-OH
and acetoacetate) are the brain and skeletal muscle. When B-OH is infused in the resting state,
its uptake by skeletal muscle shows saturation kinetics, with little further increase in B-OH up-
take between 0.8 and 1.7 mmol/L (8, 100), while higher B-OH uptake for a given arterial B-OH
concentration appears in active muscle mass (100). However, there is only limited information

about the mechanisms of ketone uptake, metabolism, and oxidation within skeletal muscle, espe-
cially at different exercise intensities and at different blood ketone levels. Tracer techniques used
in healthy males have shown that the stimulatory effect of exercise (50% of VO2max ) on the rate
of disappearance and metabolic clearance of ketones, surprisingly, became less marked as basal
ketonemia increased and it was completely abolished and even reversed when initial resting lev-
els were higher than 3–4 mmol/L (41). Supportive recent findings show that endurance-trained
athletes who ingested a drink containing ketone esters had a rapid rise in plasma B-OH concentra-
tions to ∼3 mmol/L (35, 132). During subsequent exercise at 40% of peak power output, plasma
levels of B-OH remained unchanged during exercise compared with before exercise, and there
was only a small reduction in circulating plasma B-OH during exercise at 75% of peak power
output (35). Since circulating concentrations of ketone bodies reflect the balance between the de-
livery of ketone bodies to the circulation and the disposal of ketone bodies, these findings suggest
there may be limited uptake of ketone bodies by muscle during exercise at these high initial con-
centrations. Of note is that when ketone ester drinks were ingested during the basal resting state,
resulting in a rise in blood B-OH concentrations, the plasma concentrations of glucose, FAs, and
triacylglycerol were decreased and remained so for the following 3 h (132).

Cox and coworkers (35) evaluated exercise performance in eight highly trained male endurance
athletes during a 1-h steady-state bout of bicycle exercise (at 75% of peak power output) followed
by a 30 min time trial for maximum distance after drinking ketone esters plus carbohydrates or
carbohydrates alone 10 min before exercise was initiated. The ingestion of ketone esters resulted
in an increase in plasma concentrations of B-OH to ∼2 mmol/L, and concentrations remained
elevated throughout the exercise bout. Initially, during the 1-h exercise bout, both plasma glucose
and FA concentrations were decreased after ketone body ingestion. This is in line with findings
that high plasma B-OH concentrations cause a decrease in glucose and a decrease in adipose tissue
lipolysis for several hours (100, 133). Despite these metabolic disturbances, the distance covered in
the following time trial was 2% improved after the ingestion of ketone bodies and carbohydrates
compared with ingestion of carbohydrates alone (35).
The source of ketones may be important for performance effects. Thus, when hyperketonemia
occurred after ingestion of ketone diesters (1,3-butanediol acetoacetate diester), performance on
a 31-km time trial under conditions simulating real-life competition was impaired in professional
male cyclists (2% longer time to complete the trial) despite the achievement of hyperketonemia
(87). The authors suggest that in this trial a contributing factor have been the stomach discomfort
induced by the ketone diester.
The mechanisms behind suppressed adipose tissue lipolysis resulting from increased concen-
trations of plasma B-OH are not well understood. It is interesting that when plasma concentrations
of FAs were reduced during 2 h of exercise at 70% of VO2max in endurance-trained individuals
after the ingestion of ketone bodies and carbohydrates, intramyocellular triacylglycerol content
decreased by 24% (35). These findings suggest that there is divergent regulation of lipolysis in adi-
pose tissue and skeletal muscle and, furthermore, that the availability of circulating FAs is involved
in regulating intramyocellular triacylglycerol break down, as suggested previously (75).
Based upon the limited data and the limited information on the mechanisms of ketone uptake,
metabolism, and oxidation within skeletal muscle, there is no clear evidence to support ketone
bodies as an important energy fuel for skeletal muscle during exercise. However, ketone bodies
play an important role as an alternative fuel during prolonged fasting and starvation, especially
for the brain. It has been suggested that ketone bodies may help with cognitive improvement and
improvement in neurodegenerative pathologies (148). Therefore, the central nervous system may
be another target for the performance-enhancing effects of nutritional ketosis in addition to—or
perhaps instead of—effects related to skeletal muscle metabolism.

4. DIETARY PROTEINS FOR ATHLETES

For decades, there has been discussion about how much dietary protein is ideal for athletes.
Whereas an apparent global consensus is that adults need no more than ∼0.8 g protein/kg per day
to meet their protein requirements (111), the optimal dietary protein amount for athletes remains
controversial, with suggested intakes ranging from less than (26) to up to fourfold more than that
advised for sedentary individuals (80). Most research has investigated protein requirements in tra-
ditional resistance exercise and only to a lesser extent in endurance exercise. Exercise modalities,
and their resulting protein metabolism, vary considerably between resistance and endurance exer-
cise (153). Therefore, it is necessary to discuss the optimal amount of dietary protein for resistance
and endurance exercise separately. That being said, it should be recognized that many athletes, for
example power sport athletes, fall between these two training modalities because their training
involves both types of exercise.
4.1. Resistance Exercise: Role of Dietary Protein for Strength

and Muscle Hypertrophy

Several approaches have been used to evaluate the optimal daily dietary protein intake for resis-
tance athletes. Nitrogen balance studies in resistance athletes have shown an increased require-
ment for protein when these athletes are compared with sedentary individuals (137). In novice
bodybuilders doing intense resistance exercise 6 times/week, nitrogen balance was achieved at
1.4–1.5 g/kg per day (137), whereas protein intake of 2.6 g/kg per day did not enhance muscle
mass and strength during 1 month of resistance training by more than that induced by an in-
take of 1.4 g/kg per day (137). These findings suggest an increased need for protein in resistance
athletes compared with sedentary individuals, and findings in a meta-analytic regression pointed
to the need for daily protein intake of 1.3 g/kg per day for resistance athletes to enable them to
maintain nitrogen balance (110). Nitrogen balance studies have methodological limitations (101).
That being said, these studies provide us with important knowledge about the amount of protein
needed to secure the replacement of lost protein and to prevent deficiency.
4.1.1. Studies of acute resistance exercise: muscle protein synthesis. Measuring muscle
protein synthesis (MPS) is another approach to gaining insight into protein requirements in re-
lation to resistance exercise. In the fasted resting situation without prior exercise, protein intake
acutely stimulates MPS. During rest in young individuals, intake of ∼30 g of protein increases
MPS by 50%, which is similar to an intake of ∼90 g of protein (134). Intriguingly, giving an in-
fusion of amino acids (15) or an oral bolus of protein (7) has shown that activation of MPS by
circulating amino acids is transient and returns to basal levels within approximately 2–3 h despite
continuing hyperaminoacidemia (7, 15). These transient postprandial increases in MPS are coun-
terbalanced by fluctuations in muscle protein break down (MPB), which is why simply consuming
protein in the absence of contractile activity fails to induce protein retention and skeletal muscle
hypertrophy.
In the hours following resistance exercise, muscles are more sensitive to circulating amino acids,
and the ingestion of protein stimulates MPS to a greater extent than it does during rest (19). A
relationship between the rate of MPS and ingested protein dose in a meal following resistance ex-
ercise in the fasted state has been established (94, 104, 157). When graded doses of protein from 0
to 40 g, either egg protein (104) or whey protein isolate (157), were fed to moderately resistance–
trained men immediately after an acute bout of one-legged resistance exercise performed in the
fasted state, MPS in the exercised leg increased gradually up to a protein intake of 20 g, with no

further increase thereafter. Thus, approximately 20–30 g of protein per meal seems to be a maxi-
mally effective protein dose for healthy young men both at rest (134) and after resistance exercise
(104, 157), regardless of training status (157). Of note, one study reported slight (19%) but signif-
icantly greater stimulation of MPS in the fasted state in young resistance-trained men consuming
40 g of whey protein compared with 20 g (94). In this study, whole-body resistance training was
performed (94) in contrast to the one-legged resistance training protocol in the previous studies
(104, 157). This may suggest that athletes performing whole-body resistance exercise involving
more muscle mass may benefit from a higher protein intake post-exercise.
When data from six studies in which MPS was measured over 3–4 h in young resistance-trained
participants after ingestion of protein ranging from 0 to 40 g were compared in a two-phase linear
regression model, 0.25–0.30 g of protein/kg per meal (90% confidence interval: 0.18 to 0.3) was
found to stimulate MPS maximally, both at rest and in the recovery period after acute resistance
exercise in the fasted state (but to a greater extent following exercise) (103). This emphasizes that
in a resistance-trained athlete who weighs, for example, 100 kg, MPS is maximally stimulated by
meals containing approximately 25–30 g of protein.
The upper limit to an acute effect on MPS by protein intake may be due to limitations at
several steps, from amino acid absorption in the gut to the protein synthesis process in the muscle.
When 20 g of protein is ingested, ∼45% of the amino acids are extracted by splanchnic tissues,
such as the gut and the liver, prior to it entering the peripheral circulation (131). The remainder
(∼55%) of the amino acids are released into the circulation, but only a fraction of the circulating
amino acids end up as substrates for protein synthesis in peripheral tissues. Thus, only 11% of the
amino acids provided to young men by a 20 g oral bolus of casein protein were used for whole-
body protein synthesis, despite ∼55% entering the peripheral circulation following absorption
in the gut and first pass in the liver (49). The remaining amino acids are catabolized and serve
as substrates for a range of metabolic processes, from energy production (104) to urea synthesis
(157).
4.1.2. Muscle protein break down. Focusing only on MPS may be insufficient for evaluating
protein requirements in athletes since the content of any particular muscle protein, structural or
metabolic, is the result of a balance between the rate of MPS and the rate of MPB. Little is known
about the regulation of MPB, due to methodological difficulties. An isolated focus on MPS in
the context of the protein dose needed to optimize the anabolic response to a post-exercise meal
could thus potentially underestimate the contribution of MPB suppression to positive net pro-
tein balance. Even though changes in MPS appear to be much greater (three- to tenfold) than
in MPB following acute resistance exercise, high protein intake (∼70 g) also appears to inhibit
whole-body protein break down (81). While the ingestion of 40 g and 70 g of protein follow-
ing acute resistance exercise increased MPS similarly, the whole-body net protein balance was
more positive with 70 g than with 40 g of protein, likely due to a greater suppression of whole-
body protein break down (81). In addition, a positive linear association was reported between
protein intake (from 6 g to 92 g) and whole-body net protein balance (82). This lack of a plateau
led to the suggestion that there is no absolute upper limit for protein intake in regard to the
maximization of muscle anabolism. This proposal was based on whole-body measures, and since
skeletal muscle may constitute ∼25% of whole-body proteolysis (90), it is possible that as much
as 70–90 g protein/meal will suppress MPB to an even greater extent. This could argue for the
need for a very high protein intake in athletes. However, the suppression of MPB following resis-
tance exercise will be advantageous only if inhibition applies specifically to intact myofibrillar pro-
teins. A fraction of the total exercise-induced MPB likely also comprises the degradation of dam-
aged muscle proteins or muscle proteins with rapid turnover rates, or both. This is supported by

recent findings showing activation of two cellular protein degradation and renovation processes,
macroautophagy (42) and chaperone-assisted selective autophagy (144), during endurance and
resistance exercise, respectively. These proteolytic processes are inhibited by amino acids and in-
sulin (42) and are important for muscle function and muscle maintenance because they degrade
mechanically damaged proteins (144). Degradation of proteins is likely an implicit part of the ex-
ercise adaptive response, allowing for protein remodeling and reconditioning in addition to the
synthesis of new proteins. Thus, the inhibition of MPB could be proposed to impair adaptions
to exercise training. Moreover, a number of longitudinal exercise training studies have reached
the conclusion that in untrained participants, exercise training actually reduces protein utilization
and requirements due to a more efficient use of amino acids derived from MPB (53). This could
point toward the provocative suggestion that even lower amounts of dietary protein are needed
by athletes compared with beginners. Until more information accumulates on the role of MPB of
specific proteins in muscle remodeling, recommendations for dietary protein amounts to enhance
training adaptations in resistance athletes should focus primarily on the response of MPS, as well
as on functional and anthropometric responses to resistance exercise training.
4.1.3. Studies of chronic resistance exercise training. One question is whether changes in
MPS obtained with protein intake following acute resistance exercise relate to the magnitude of
muscle hypertrophy in longer-term training studies. In a within-participant study, MPS rates mea-
sured after protein intake following acute resistance exercise did not correlate with hypertrophy in
the same participants after 16 weeks of resistance training (102). Another study also found a lack of
association between the MPS rate after acute resistance exercise and hypertrophy after 16 weeks
of resistance training, but it did detect some modest correlations between activation after acute
resistance exercise of Akt/mammalian target of rapamycin complex 1(mTORC1)/ribosomal pro-
tein S6 kinase beta-1(p70S6K) signaling for protein translation and muscle hypertrophy after 16
weeks of resistance exercise (96). Nonetheless, these findings highlight the pitfalls in evaluating
the role of protein intake on MPS rates following acute resistance exercise as seeming to indicate
hypertrophy in response to resistance training.
In one long-term study, 6 weeks of resistance exercise training in trained participants led to
an increase in lean tissue mass (+2.3 kg, or 3.8%) when 2.1 g/kg per day of protein was ingested,
whereas resistance training did not change lean tissue mass when 1.2 g/kg per day was ingested
(20). This could suggest that more than 1.2 g/kg per day is needed to achieve hypertrophy with
resistance exercise training. Of note is that in trained individuals, a protein intake of 3.4 g/kg
per day was not superior to 2.3 g/kg per day for resistance training–induced strength and lean
body mass accretion after 8 weeks (3), and supplementation with leucine metabolites on top of
the 2.2 g/kg per day intake had no further effect on training-induced strength or cross-sectional
muscle thickness (138). When several resistance-training studies with varying protein intakes were
subjected to meta-analysis, protein intake up to 1.6 g/kg per day was sufficient to increase resis-
tance training–induced gains in fat-free mass by an average of 27% (∼0.3 kg muscle mass) (106),
consistent with findings in a previous meta-analysis (31). It is noteworthy that beyond a daily pro-
tein intake of 1.6 g/kg per day (95% confidence interval: 1.0 to 2.2), there was no further increase
in resistance training–induced fat- free mass (106). This highlights the fact that resistance exer-
cise athletes aiming at hypertrophy can reach maximal effect with an intake of 1.6 g/kg per day
of dietary protein. Quite paradoxically, most individuals already consume protein amounts at this
level or above. In athletes, daily intakes of protein from 1.2 to 2.3 g/kg per day in male and 0.8 to
1.7 g/kg per day in female team sport athletes have been observed (64), whereas intakes of 3.2 g/kg
per day for males and 2.5 g/kg per day for females were seen in strength and power athletes (127),
which is why most resistance athletes already get sufficient amounts of protein in their habitual

diet to optimally stimulate hypertrophy with training. It should be emphasized that the magnitude
of hypertrophy and the adaptions that are attributable to the amount of dietary protein intake ap-
pear to be relatively small when compared with the overall improvements made as a result of the
resistance exercise training itself. Thus, exercise is the greatest stimulus for MPS.
4.2. Endurance Exercise: Role of Dietary Protein in Performance

and Training Adaptions
The optimal protein intake for endurance athletes has received less attention than it has for re-
sistance athletes. It is known that endurance athletes need to ingest more dietary protein than
sedentary individuals to reach nitrogen balance, which is achieved at 1.2–1.4 g/kg per day (136).
An increased need for protein to maintain nitrogen balance is likely most pronounced during the
initiation of endurance exercise training periods, which is emphasized by the findings that those
who undertake unaccustomed endurance exercise for 3 weeks and consume 1.0 g of protein/kg
per day had a negative nitrogen balance during the first few days, but improved over time and
returned to pretraining levels after 3 weeks under conditions of constant protein intake (46). Dur-
ing intense training periods, protein needs may also be higher in well-trained athletes. In a recent
study, endurance-trained athletes were subjected to 2 days of controlled diet (1.4 g of protein/kg
per day) and running training (10 and 5 km/day on day 1 and 2, respectively) (77). On the third day,
athletes ingested a range of different protein intakes (0.2–2.8 g/kg per day) and sufficient energy to
reach energy balance in the hours after 20 km of running in the fasted state (77). The protein intake
to establish whole-body protein balance during recovery from the 20 km run was estimated with
a technique based on 13 C-labeled phenylalanine infusion and subsequent measurement of 13 CO2
excretion (77). Based on these measurements, the protein requirement was 1.65 g/kg per day and
the recommended protein intake was1.83 g/kg per day to cover the metabolic demand for protein
on higher-volume training days (77). Nonetheless, it is unclear whether these protein targets are
optimal with respect to performance outcomes and whether these whole-body measures reflect
muscle protein metabolism and endurance training adaptions. However, collectively it seems as if
both during the initiation of endurance training in untrained individuals and also during intensi-
fied or high-volume training periods in well-trained participants, the protein requirement is likely
increased compared with sedentary or more moderate training periods.
Another approach to evaluate protein needs in endurance athletes relates to estimating the
amount of protein oxidized during exercise that potentially needs to be replenished afterward.
Branched-chain amino acids (isoleucine, leucine, and valine) are the amino acids that are prefer-
entially oxidized in skeletal muscle (136). Leucine is the most well studied and has been shown to
be oxidized to a minor extent (approximately 2–10% of energy consumption) during endurance
exercise, depending on training status, sex, prior food intake, pre-exercise muscle glycogen con-
tent, and exercise intensity and duration (136). Because the oxidation of leucine is lower in trained
compared with untrained athletes at rest (85) and also during moderate exercise intensity at 65%
of VO2max (98), it could be hypothesized that the relative contribution of amino acids to substrate
oxidation is decreased with training. In congruence with these findings, endurance-trained indi-
viduals were better at nitrogen retention during energy deficit or low protein intake (0.57g/kg per
day) compared with sedentary individuals (26). In the training studies discussed above, the exercise
volume and intensity were low, which is why further studies are required to confirm whether im-
proved protein utilization and nitrogen retention also appear in athletes performing high-intensity
exercise.
Studies of acute endurance exercise have shown that MPS can be increased sixfold after en-
durance exercise in the fasted state by the ingestion of as little as 10 g of protein compared with

continued fasting (88). Moreover, the ingestion of 10 g of whey protein immediately and 30 min
after a single bout of endurance exercise enhanced the myofibrillar MPS rate but not the MPS rate
for mitochondrial proteins, when measured 4 h following exercise (17). Carbohydrate intake stim-
ulates insulin release, which can enhance protein synthesis and, importantly, suppress proteolysis
in muscle (12). However, protein and carbohydrate co-intake was found to be superior to the con-
sumption of isoenergetic amounts of carbohydrates alone to stimulate MPS after acute endurance
exercise (17). Therefore, protein intake and potentially also the intake of carbohydrates follow-
ing endurance exercise seems to enhance MPS acutely, and this has been used as an argument to
suggest that endurance athletes should consume 20 g of protein in the immediate post-exercise
period (146).
The measurement of total MPS rates represents myofibrillar proteins, as well as metabolic and
mitochondrial proteins. Whereas myofibrillar MPS is crucial for muscle hypertrophy in resistance
athletes, endurance athletes instead aim for optimal training-induced metabolic and mitochon-
drial protein adaptations in muscle. Interestingly, in endurance-trained participants, compared
with placebo, the ingestion of 28 g of protein and 50 g of maltodextrin increased only myofib-
rillar, but not mitochondrial, MPS after an acute sprint cycling exercise (34). Consequently, total
MPS rates after acute endurance exercise may not be the best comparison for evaluating the opti-
mal amount of dietary protein for metabolic and mitochondrial adaptions to endurance training.
This is also supported at a molecular level since it appears that 100 min of high-intensity, aero-
bic interval exercise in the fasted state increased activity of the Akt/mTORC1/p70S6K signaling
pathway to a similar extent as resistance exercise did (124). However, at the same time, in mice,
mitochondrial and myofibrillar MPS rates were increased for up to 6 h following acute endurance
exercise, despite prolonged suppression of mTORC1 activity in skeletal muscle (112). This is in
contrast to acute resistance exercise in which increases in MPS require mTORC1 activity. Pro-
tein ingestion and enhanced total MPS and Akt/mTORC1/p70S6K signaling may not be crucial
for metabolic adaptations associated with endurance training. Also, the transcriptional induction
of endurance exercise–induced metabolic and mitochondrial proteins is mediated by signaling
pathways related to cellular energy and oxidative stress, such as AMPK signaling and reactive
oxygen species levels (see the sidebar titled, Role of Diet in Regulating Reactive Oxygen Species–
Mediated Muscle Training Adaptations in Athletes), and it is stimulated to a greater extent during
periods of low compared with high energy availability and muscle glycogen content (114). Taken
together, there is a lack of sufficient evidence to evaluate the amount of dietary protein needed
to optimally stimulate muscle metabolic adaptions to endurance training, which calls for further
investigation.
4.3. Timing of Dietary Protein Intake for Adaptations Due

to Resistance Training
The necessity of and possible benefits from consuming protein immediately after the termination
of exercise have been debated for many years. A single bout of resistance exercise in the fasted
state seems to potentiate MPS in response to protein intake, which may persist for 24–48 h in
untrained (19) and for 8–16 h in trained participants (83). In young untrained individuals, the in-
gestion of 20 g of whey protein either before or 1 h after 10 sets of leg extensions resulted in similar
rates of amino acid uptake (140), and MPS was increased to the same extent as when protein was
ingested 1 h or 3 h after resistance exercise (118). This could point to the timing of protein in-
take having no major role immediately post-exercise, at least as judged by the MPS rate measured
after acute exercise. Some (37, 156) but not all (63) training studies have reported greater resis-
tance training–induced increases in lean mass when protein intake occurred in close proximity

ROLE OF DIET IN REGULATING REACTIVE OXYGEN SPECIES–MEDIATED

MUSCLE TRAINING ADAPTATIONS IN ATHLETES
Acute exercise induces moderate and transient increases in reactive oxygen species (ROS) in skeletal muscle.
Exercise-induced ROS are required for normal force production in muscle, while high levels of ROS appear to pro-
mote contractile dysfunction (116). Also, exercise-induced ROS production is important for training-induced mito-
chondrial biogenesis, including cytosolic-derived ROS production (61), because ROS serve as signaling molecules
to activate redox-sensitive signaling pathways (116). Accordingly, there is a growing body of literature suggesting
that antioxidant supplementation seems to hamper or prevent muscle training adaptations, such as mitochondrial
biogenesis and hypertrophy.
The macronutrient content of the diet can affect ROS levels in muscle. Thus, in rats, the overconsumption of a
high-fat, high-sucrose diet induced muscle oxidative stress in a fiber type–dependent manner (115), and in mice, this
diet also mediated ROS-induced mitochondrial biogenesis in muscle (72). In humans, a 1,000 kcal carbohydrate-
rich meal, but not a fat-rich meal, induced oxidative stress responses in serum and muscle (48). However, little is
known about the role of macronutrient composition in athletes’ diets in the regulation of ROS-mediated muscle
training adaptions. This also relates to the inadequacy of the methods that available for measuring oxidative stress
and ROS levels in skeletal muscle.
to resistance exercise (e.g., close to starting or stopping) compared with several hours following
the exercise. A recent review (4) and a meta-analysis (125), both of which included studies that
have investigated the timing of protein intake (i.e., defined as consumption of ≥6 g of protein
1 h pre- and/or post-resistance exercise versus ingestion >2 h pre- and/or post-resistance exer-
cise), refuted that timing was critical to resistance training–induced gain in strength and fat-free
mass. This conclusion was later questioned due to potential bias related to poorly matched groups
and a wide range of habitual protein intake between groups. Nonetheless, because no convincing
evidence exists to conclude there is a beneficial effect of consuming protein immediately after re-
sistance exercise, it could be hypothesized that it is more important to ensure frequent intake of
sufficient protein. This is based on a study showing greater rates of MPS in trained men in the
12 h following resistance exercise after ingestion of 20 g of protein every 3 h when compared with
ingestion of 40 g of protein every 6 h and 10 g of protein every 1.5 h (5). Moreover, to maximally
stimulate nocturnal MPS and inhibit MPB, consuming protein prior to sleep may be beneficial.
Thus, ingesting up to 0.6 g/kg before sleep following resistance exercise was shown to augment
both overnight MPS (121) and chronic muscle adaptations to resistance training (128). To our
knowledge, the effect of the timing of protein intake following endurance exercise and its role in
adaptations to endurance exercise training have never been directly assessed.
4.4. Sources and Types of Proteins

It has been suggested that the type (i.e., source) of protein consumed may affect the anabolic re-
sponse, especially to resistance exercise, whereas there has been less investigation of this in relation
to endurance exercise. The majority of studies have evaluated various types of protein and their ef-
fect on MPS, whereas few studies have investigated the effect on MPB or functional aspects. Also,
most findings are based on an acute intake of different protein sources, focusing on the effect on
MPS in the hours after ingestion, and only a few studies have evaluated the effect of different
protein types consumed regularly over time in combination with exercise training.

Proteins from various animal sources, such as milk, beef, and egg protein, and also plant-based
protein, such as soy protein, have been compared to determine to what extent they affect MPS
at rest and after acute resistance exercise. Milk proteins especially have been extensively inves-
tigated, and both whole and fat-free milk have been shown to potently stimulate MPS 1 h after
resistance exercise in young men (40). Interestingly, dairy protein seems to offer some advantages
for muscle anabolism over other protein types. Following resistance exercise, MPS was found to
be greater with the ingestion of low-fat milk compared with the consumption of an isonitrogenous
soy protein drink (154). Also, 30 g of milk protein compared with 30 g of beef protein stimulated
post-exercise MPS to a greater extent (18). Milk contains both whey and casein, and whey seems
especially potent in acutely stimulating MPS, since the ingestion of whey protein following re-
sistance exercise was found to be superior to matched amounts of both casein and soy protein in
increasing MPS (135). In addition to the acute studies, one long-term study demonstrated that
fat-free milk compared with soy protein ingested following each bout of resistance exercise dur-
ing 12 weeks of training led to greater gains in muscle mass and strength in novice weightlifters
(54).
The degree to which various types of proteins stimulate MPS seems to relate to the amount of
essential amino acids (EAAs) in the protein. EAAs appear to be crucial for stimulating MPS and
obtaining positive net muscle protein balance following resistance exercise (141); this is supported
by the finding that in young men, consuming 6 g of EAAs stimulated MPS twice as much as
consuming a mixture of 3 g of non-EAAs plus 3 g of EAAs (16). In particular, the branched-chain
amino acid leucine seems to be unique among the EAAs as a regulator of protein translation
initiation (2), as emphasized by the finding that ingesting a protein blend of whey:casein:soy (in a
ratio of 1:2:1) is as effective in stimulating MPS as ingesting whey protein alone that is matched
for leucine content (120). Accordingly, participants ingesting 25 g of whey protein or 6.25 g whey
protein with 5 g leucine added (to induce similar leucine availability) showed similar induction
of MPS, both at rest and after resistance exercise (32), thus signifying the importance of leucine
for maximal stimulation of MPS. However, 6.25 g of leucine alone was insufficient to stimulate
MPS as compared with a similar amount of whey protein matched for leucine content (33), and
this is why providing other amino acids and, in particular, EAAs seems necessary to fully stimulate
MPS. This is why egg protein, which is often seen as a complete, high-quality protein because it
contains all of the EAAs, along with milk and beef have been suggested for athletes; all have been
shown to increase MPS after resistance exercise in young men (104).
In addition to EAA and leucine content, the absorption properties of various protein types may
contribute to differences in MPS responses. A rapid appearance of amino acids in the circulation
seems to be crucial for a maximal MPS response (152), and this likely contributes to the superiority
of whey to acutely increase MPS (135). However, the ingestion of more slowly absorbed protein
types, such as casein, results in a more moderate but prolonged hyperaminoacidemia, which might
be beneficial prior to sleep to attenuate negative whole-body net protein balance during nocturnal
fasting conditions (121, 128).
In general, when compared with plant proteins, protein from animal sources seems more ben-
eficial for athletes to stimulate MPS, especially when animal-based proteins are compared with
soy protein (71). However, not all plant-based proteins may be inferior to protein from animal
sources, which was highlighted by the finding that leucine from rice protein seems to have unique
absorption kinetics, and supplementation with 48 g of rice or whey protein after each bout of
exercise training stimulated gains in strength and hypertrophy to a similar extent in response to
8 weeks of resistance training in young men (76). Most foods contain several protein types, and
combining protein types is likely beneficial for muscle protein balance, although this needs to be
investigated further.

SUMMARY POINTS
1. Nutritional recommendations for athletes have not changed markedly during the past
decade, but improved methods and scientific advances have increased our understand-
ing of the physiological and molecular mechanisms of dietary interactions with training
adaptations and led to more nuanced recommendations.
2. Athletes should aim to consume enough carbohydrates to meet the requirements of
their training program and to optimize the replenishment of muscle glycogen stores
between workouts. Appropriately timing the intake of carbohydrate-rich foods and bev-
erages with a high-to-moderate glycemic index can provide a readily available source of
carbohydrates for muscle glycogen synthesis.
3. The daily diet of most athletes comprises ample amounts of protein, and there is no clear
evidence to support the idea that consuming more than ∼1.6 g/kg per day of dietary
protein will further increase resistance training–induced hypertrophy.
4. In the recovery period from exercise, consuming frequent meals ensures optimal mus-
cle glycogen and protein synthesis due to persistently high plasma glucose, insulin, and
amino acid availability. During recovery, muscle glycogen resynthesis is maximally stim-
ulated by the intake of ∼1.2 g carbohydrate/kg per hour, whereas maximal stimulation of
muscle protein synthesis seems to occur at intakes of approximately 0.25–0.30 g protein/
kg per meal.
5. It appears that steady-state exercise at low-to-moderate intensity can be maintained after
adaptation to a ketogenic or nonketogenic high-fat diet, at least on a shorter-term basis.
However, for exercise at higher intensities, which is relevant for many endurance athletes,
a diet high in fat is inferior to a diet high in carbohydrates in improving performance
in response to a training intervention. High-fat diets seem to impair rather than spare
carbohydrate utilization during exercise.
6. It takes time for the body to adapt to utilize ketone bodies as an energy source and there
is no clear evidence to support ketone bodies as an important energy fuel for skeletal
muscle during exercise. However, the central nervous system may be a target for the
performance-enhancing effects of nutritional ketosis.
7. General dietary recommendations for athletes can be provided, but they should be fine-
tuned to individual considerations. An athlete’s diet should never be static: It should be
composed in accordance with the requirements of the training program.
FUTURE ISSUES
1. It appears that trained participants can achieve ∼100% greater glycogen synthesis rates
than untrained participants. Does this relate only to the intrinsic properties of muscle or
is gastrointestinal absorption or the splanchnic extraction of glucose, or both, subject to
adaptations with exercise training?
2. The role of the glycogen content in the brain for exercise performance has recently
received attention in the scientific literature. The dietary regulation of brain glycogen
levels and the importance of brain glycogen for exercise performance and fatigue await

further studies. To this end, human studies using isotopic labeling techniques or spec-
troscopy would be highly valuable.
3. What are the effects of high-fat diets for resistance athletes and in sports in which total
glycogen availability is less important?
4. What are the direct effects of ketone bodies on skeletal muscle? To what extent are
they taken up in skeletal muscle during exercise? And are the eventual performance-
enhancing effects of ketone supplementation mediated via central mechanisms?
5. The amount of dietary protein required to optimally stimulate metabolic adaptions in
muscle to endurance exercise training and to improve endurance performance should be
addressed in exercise training studies in well-trained athletes. Along this line, is there a
positive or negative effect of timing protein intake to be in close proximity to endurance
exercise for subsequent metabolic adaptations?
6. Research into the regulation of muscle protein break down during and after exercise, in-
cluding both the ubiquitin–proteasome system and the autophagy system, together with
research into the effects of diet on protein break down for adaptations to exercise train-
ing are necessary to fully understand the role of dietary protein in regulating training
adaptions.
7. Long-term studies that compare various protein types and the concomitant response
to an exercise training intervention are needed, and future studies should address
whether blends of protein types can be manipulated to afford a favorable combination of
leucine, essential amino acids, and other dietary constituents to enable athletes to opti-
mize performance and training adaptions in response to both resistance and endurance
training.
8. Most studies on diet and performance have been conducted in males. However, because
sex differences appear in substrate utilization during exercise, more research in females
may clarify whether female athletes would benefit from different dietary recommenda-
tions than males to optimize their outcomes from exercise training.
DISCLOSURE STATEMENT
The authors are not aware of any affiliations, memberships, funding, or financial holdings that
might be perceived as affecting the objectivity of this review. B.K. was funded by the Danish Med-
ical Research Council, the Lundbeck Research Foundation, the Novo Nordisk Research Foun-
dation, and the University of Copenhagen’s Excellence Program for Interdisciplinary Research
(2016 for the grant, Physical Activity and Nutrition for Improvement of Health). The postdoctoral
fellowships of A.M.F. and A.M.L. were supported by a research grant from the Danish Diabetes
Academy (grant number NNF17SA0031406), which is funded by the Novo Nordisk Foundation,.
A.M.F. was further supported by the Alfred Benzon Foundation.
ACKNOWLEDGMENTS
The authors apologize to all those whose contributions to the field could not be cited due to space
and reference limitations.

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NU39CH10_Kiens ARjats.

cls May 20, 2019 13:23

Annual Review of Nutrition

Faculty of Science, University of Copenhagen, Copenhagen 2200, Denmark;

Annu. Rev. Nutr. 2019. 39:10.1–10.29 Keywords

3.2. Exercise Performance After Increased Ingestion of Dietary Fat . . . . . . . . . . . . . . 10.9

10.2 Fritzen • Lundsgaard • Kiens

2. DAILY CARBOHYDRATE INTAKE FOR ATHLETES: REQUIREMENTS

2.2. Mechanisms Favoring Glycogen Replenishment After Exercise

www.annualreviews.org • Dietary Fuels in Athletic Performance 10.3

glycogen synthesis rate at 4 h post-exercise (69), while a 2 h delay in intake of a carbohydrate-

0 0.5 1.0 1.5 2.0 2.5

10.4 Fritzen • Lundsgaard • Kiens

2.4. Limitations on the Muscle Glycogen Synthesis Rate

2.5. The Glycemic and Insulinemic Potential of Carbohydrates

www.annualreviews.org • Dietary Fuels in Athletic Performance 10.5

2.6. Fructose in the Post-Exercise Diet

2.7. The Daily Window for Carbohydrate Intake

10.6 Fritzen • Lundsgaard • Kiens

2.8. The Importance of Restoring Glycogen Content Before Exercise

www.annualreviews.org • Dietary Fuels in Athletic Performance 10.7

3. DIETARY FAT FOR ATHLETES

3.1. Adaptions to Exercise Training and a High-Fat Diet

10.8 Fritzen • Lundsgaard • Kiens

3.2. Exercise Performance After Increased Ingestion of Dietary Fat

www.annualreviews.org • Dietary Fuels in Athletic Performance 10.9

3.3. Mechanisms Underlying Impaired Endurance Performance

10.10 Fritzen • Lundsgaard • Kiens

3.4. Ketogenic Aids

www.annualreviews.org • Dietary Fuels in Athletic Performance 10.11

triacylglycerol were decreased and remained so for the following 3 h (132).

10.12 Fritzen • Lundsgaard • Kiens

4. DIETARY PROTEINS FOR ATHLETES

4.1. Resistance Exercise: Role of Dietary Protein for Strength

and Muscle Hypertrophy

www.annualreviews.org • Dietary Fuels in Athletic Performance 10.13

10.14 Fritzen • Lundsgaard • Kiens

www.annualreviews.org • Dietary Fuels in Athletic Performance 10.15

4.2. Endurance Exercise: Role of Dietary Protein in Performance

10.16 Fritzen • Lundsgaard • Kiens

4.3. Timing of Dietary Protein Intake for Adaptations Due

www.annualreviews.org • Dietary Fuels in Athletic Performance 10.17

ROLE OF DIET IN REGULATING REACTIVE OXYGEN SPECIES–MEDIATED

4.4. Sources and Types of Proteins

10.18 Fritzen • Lundsgaard • Kiens

www.annualreviews.org • Dietary Fuels in Athletic Performance 10.19

10.20 Fritzen • Lundsgaard • Kiens

www.annualreviews.org • Dietary Fuels in Athletic Performance 10.21

10.22 Fritzen • Lundsgaard • Kiens

www.annualreviews.org • Dietary Fuels in Athletic Performance 10.23

10.24 Fritzen • Lundsgaard • Kiens

www.annualreviews.org • Dietary Fuels in Athletic Performance 10.25

postexercise oxygen consumption in healthy young subjects. Metabolism 35:425–29

10.26 Fritzen • Lundsgaard • Kiens

www.annualreviews.org • Dietary Fuels in Athletic Performance 10.27

of protein requirements for trained strength athletes. J. Appl. Physiol. 73:1986–95

10.28 Fritzen • Lundsgaard • Kiens

www.annualreviews.org • Dietary Fuels in Athletic Performance 10.29

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