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Chronic oral ingestion of L-carnitine and carbohydrate

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 J Physiol 589.4 (2011) pp 963–973 963

Chronic oral ingestion of L-carnitine and carbohydrate

increases muscle carnitine content and alters muscle
fuel metabolism during exercise in humans
Benjamin T. Wall, Francis B. Stephens, Dumitru Constantin-Teodosiu, Kanagaraj Marimuthu,
Ian A. Macdonald and Paul L. Greenhaff
School of Biomedical Sciences, University of Nottingham Medical School, Queen’s Medical Centre, Nottingham NG7 2UH, UK

Non-technical summary After 30 years of endeavour, this is the first study to show that muscle
carnitine content can be increased in humans by dietary means and, perhaps more importantly,
that carnitine plays a dual role in skeletal muscle fuel metabolism that is exercise intensity
dependent. Specifically, we have shown that increasing muscle total carnitine content reduces
The Journal of Physiology

muscle carbohydrate use during low intensity exercise, consistent with an increase in muscle
lipid utilisation. However, during high intensity exercise muscle carnitine loading results in a
better matching of glycolytic, pyruvate dehydrogenase complex and mitochondrial flux, thereby
reducing muscle anaerobic energy generation. Collectively, these metabolic effects resulted in a
reduced perception of effort and increased work output during a validated exercise performance
test. These findings have significant implications for athletic performance and pathophysiological
conditions where fat oxidation is impaired or anaerobic ATP production is increased during
exercise.

Abstract We have previously shown that insulin increases muscle total carnitine (TC) content
during acute I.V. L-carnitine infusion. Here we determined the effects of chronic L-carnitine and
carbohydrate (CHO; to elevate serum insulin) ingestion on muscle TC content and exercise
metabolism and performance in humans. On three visits, each separated by 12 weeks, 14
healthy male volunteers (age 25.9 ± 2.1 years, BMI 23.0 ± 0.8 kg m−2 ) performed an exercise
test comprising 30 min cycling at 50% V̇O2 max , 30 min at 80% V̇O2 max , then a 30 min work output
performance trial. Muscle biopsies were obtained at rest and after exercise at 50% and 80% V̇O2 max
on each occasion. Following visit one, volunteers ingested either 80 g of CHO (Control) or 2 g
of L-carnitine-L-tartrate and 80 g of CHO (Carnitine) twice daily for 24 weeks in a randomised,
double blind manner. All significant effects reported occurred after 24 weeks. Muscle TC increased
from basal by 21% in Carnitine (P < 0.05), and was unchanged in Control. At 50% V̇O2 max , the
Carnitine group utilised 55% less muscle glycogen compared to Control (P < 0.05) and 31%
less pyruvate dehydrogenase complex (PDC) activation compared to before supplementation
(P < 0.05). Conversely, at 80% V̇O2 max , muscle PDC activation was 38% higher (P < 0.05), acetyl-
carnitine content showed a trend to be 16% greater (P < 0.10), muscle lactate content was 44%
lower (P < 0.05) and the muscle PCr/ATP ratio was better maintained (P < 0.05) in Carnitine
compared to Control. The Carnitine group increased work output 11% from baseline in the
performance trial, while Control showed no change. This is the first demonstration that human
muscle TC can be increased by dietary means and results in muscle glycogen sparing during
low intensity exercise (consistent with an increase in lipid utilisation) and a better matching of
glycolytic, PDC and mitochondrial flux during high intensity exercise, thereby reducing muscle


C 2011 The Authors. Journal compilation 
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964 B. T. Wall and others J Physiol 589.4

anaerobic ATP production. Furthermore, these changes were associated with an improvement in
exercise performance.
(Resubmitted 25 October 2010; accepted after revision 31 December 2010; first published online 4 January 2011)
Corresponding author B. T. Wall: Department of Human Movement Sciences, Maastricht University, Maastricht, 6200
MD, the Netherlands. Email: benjamin.wall@maastrichtuniversity.nl

Abbreviations CHO, carbohydrate; CoASH, free co-enzyme A; CPT1, carnitine palmitoyl-transferase 1; PDC,
pyruvate dehydrogenase complex; TC, total carnitine; V̇O2 max , maximal oxygen uptake.

Introduction intensities >70% of maximal oxygen consumption

(V̇O2 max ; van Loon et al. 2001), we demonstrated that
More than 95% of the body’s carnitine pool is confined an acute 15% increase in muscle carnitine content
to skeletal muscle, where it fulfils two major metabolic reduced insulin-mediated muscle glycolytic flux and
roles. Firstly, in mitochondrial fatty acid translocation PDCa compared to control. Furthermore, this was
carnitine is a substrate for carnitine palmitoyl-transferase accompanied by a subsequent increase in muscle
1 (CPT1) (Fritz & McEwen, 1959; Fritz & Yue, 1963). glycogen and long-chain acyl-co-enzyme A accumulation
Secondly, during high intensity exercise, the formation (Stephens et al. 2006b), pointing to a carnitine-mediated
of acetylcarnitine is essential for the maintenance of increase in muscle fatty acid oxidation and CHO storage.
a viable pool of free co-enzyme A (CoASH), thereby Free carnitine availability may therefore be limiting to
enabling PDC and TCA flux to continue (Childress & mitochondrial fatty acid translocation even at rest and
Sacktor, 1966; Harris et al. 1987; Constantin-Teodosiu during low intensity exercise, and an increase in skeletal
et al. 1991a). Not surprisingly therefore, oral carnitine muscle TC content would be expected to augment fatty
feeding has been advocated as an ergogenic aid, the main acid oxidation and decrease PDCa and glycogen use during
premise being that increasing muscle carnitine content will low intensity exercise.
increase muscle fat oxidation and delay muscle glycogen During high intensity exercise, the primary functional
depletion. However, we are aware of no study that has role of carnitine shifts towards acetyl group buffering
unequivocally shown carnitine feeding can impact on (i.e. forming acetylcarnitine) and maintaining a pool of
muscle fuel metabolism or exercise performance, which is free CoASH which is essential for mitochondrial flux to
undoubtedly attributable to carnitine ingestion (or indeed continue (including the PDC reaction). However, during
I.V. carnitine infusion) per se failing to increase muscle
exercise of this nature there is still an increase in the
carnitine content (Barnett et al. 1994; Vukovich et al. 1994; acetyl-co-enzyme A (acetyl-CoA)/CoASH ratio, possibly
Wächter et al. 2002; Stephens et al. 2006a). due to the significant depletion (to <6 mmol (kg dry
In a series of I.V. infusion studies, we demonstrated that muscle)−1 ) of the free carnitine pool caused by acetyl-
elevating serum insulin concentration in the presence of carnitine formation (Harris et al. 1987; van Loon et al.
hypercarnitinaemia (550–600 μmol l−1 ) acutely increased 2001). Therefore, it is plausible that an increase in skeletal
muscle total carnitine (TC) content by ∼15% in humans muscle TC content would provide more effective buffering
(Stephens et al. 2006a,b). Furthermore, this increase in of acetyl-CoA production during high intensity exercise,
carnitine retention occurred only when serum insulin offsetting the increase in the acetyl-CoA/CoASH ratio,
concentration was elevated above 50 mU l−1 , which we and thereby increasing PDC flux and mitochondrial ATP
confirmed could be achieved by combined carbohydrate production. This in turn would reduce the contribution
(CHO) and L-carnitine feeding (94 g and 3 g, respectively), from glycolysis and PCr hydrolysis to ATP production,
albeit at a much lower rate of retention (equating to a particularly during the rest to exercise transition period
projected ∼0.1% increase in the muscle TC pool per day; when inertia in mitochondrial ATP production is known
Stephens et al. 2007). Assuming this effect of combined to reside at the level of PDC activation and flux (Timmons
CHO and carnitine feeding on carnitine retention is et al. 1997, 1998; Howlett et al. 1999; Roberts et al.
sustainable and cumulative, it was calculated that about 2002, 2005). In addition, increasing PDC flux during
24 weeks of feeding would be needed to increase skeletal high intensity exercise would be expected to decrease
muscle TC content to the same extent as acute I.V. carnitine muscle lactic acid production which could translate to
and insulin infusion. a positive effect on exercise performance by reducing
During low intensity exercise, when PDC activation muscle acidosis (Sahlin, 1992). In support of this stance,
(PDCa) and flux are relatively low, the principal role previous work from our laboratory has shown that
of carnitine will most likely be mitochondrial fatty pharmacological activation of PDC at rest using the
acid translocation. Although it has been suggested pyruvate dehydrogenase kinase inhibitor, dichloroacetate,
that free carnitine only limits fat oxidation at exercise


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J Physiol 589.4 Muscle carnitine loading and fuel utilisation 965

markedly reduced muscle lactate production and PCr and a continuous and incremental, exhaustive exercise
hydrolysis during a subsequent 20 min period of intense protocol. Oxygen consumption was measured using an
muscle contraction in isolated and perfused canine skeletal online gas analyser (Vmax; SensorMedics, Anaheim, CA,
muscle, resulting in a substantial improvement in tension USA) and V̇O2 max was confirmed during a repeat test
development (Timmons et al. 1997). 3 days later. V̇O2 max was accepted when a plateau in oxygen
Based upon the above information, it is logical to consumption was achieved despite a further increase in
conclude that increasing skeletal muscle TC content could workload. Once V̇O2 max had been obtained, workloads to
alter muscle fuel metabolism in at least two different ways be used in subsequent experimental visits were calculated
during exercise, with the dominating role being dictated by that would elicit 50% and 80% of V̇O2 max . Subjects
the exercise intensity employed. With this in mind, we first were familiarised with the experimental exercise protocol
aimed to determine whether chronic L-carnitine and CHO (which also allowed confirmation that the workloads
feeding to healthy male volunteers could increase skeletal were at the appropriate intensity to elicit 50% and
muscle TC content in a manner similar to that which 80% V̇O2 max ) at least 1 week prior to the beginning of
we have observed acutely under I.V. L-carnitine infusion subsequent experimental visits. A repeat V̇O2 max test was
and hyperinsulinaemic clamp conditions. Secondly, we also performed at least 1 week after the completion of the
hypothesised that any increase in muscle TC content study to confirm no significant change in aerobic capacity
would result in a blunting of PDCa and flux during low had occurred over the course of the study.
intensity exercise, causing a corresponding decrease in
muscle glycogen utilisation. Thirdly, during high intensity
exercise, when the primary functional role of carnitine Experimental protocol
switches to acetyl group buffering, we proposed that
Volunteers reported to the laboratory at 08.30 h on three
increasing muscle carnitine content would increase muscle
occasions over a 24 week period, each visit being separated
PDC flux (and mitochondrial ATP delivery), thereby
by 12 weeks. Subjects arrived after an overnight fast
reducing anaerobic ATP production and muscle lactic
having abstained from strenuous exercise and alcohol
acidosis during exercise. Finally, we hypothesised that
consumption for at least 48 h, and caffeine for at least
these positive metabolic effects of muscle carnitine loading
24 h. On each visit, subjects performed the following
would improve high intensity exercise performance.
experimental protocol. On arrival at the laboratory,
subjects were weighed and then rested in a semi-supine
position whilst a resting blood sample was collected
Methods from an antecubital vein (venipuncture) for blood
Human volunteers glucose, serum insulin and plasma TC concentration
measurements. Volunteers then exercised for 30 min on
Fourteen healthy, non-smoking, non-vegetarian the cycle ergometer at a workload corresponding to 50%
recreational athletes (V̇O2 max 51.6 ± 2.5 ml (kg body V̇O2 max followed immediately by 30 min of exercise at a
mass)−1 , training 3–5 times per week in triathlon, predetermined workload of 80% V̇O2 max . During both
cycling, running or swimming), aged 25.9 ± 2.1 years bouts of exercise, a rating of perceived exertion (Borg
and with a body mass index (BMI) of 23.0 ± 0.8 kg m−−2 Scale) was obtained every 10 min. Finally, immediately
participated in this study. Moderately trained recreational following the completion of exercise at 80% V̇O2 max ,
athletes were recruited as they were accustomed to subjects performed a 30 min work output performance
ingesting CHO supplements. The study was approved test. This ‘all-out’ performance test involved using the
by the University of Nottingham Medical School Ethics ergometer hyperbolic mode function, where work output
Committee in accordance with the Declaration of Helsinki. is dependent upon volitional cycling cadence. This
Prior to the study, each subject completed a routine performance test has been shown to be a more reliable
medical screening and a general health questionnaire measurement of endurance exercise performance than
to ensure their suitability to take part. All gave their cycling at a fixed exercise workload to volitional exhaustion
informed written consent to participate in the study and (Jeukendrup et al. 1996), and has been used previously in
were aware that they were free to withdraw from the our laboratory to measure performance (Stephens et al.
experiment at any point. 2008).

Pre-testing Supplementation protocol

Fourteen days before the trial, each subject’s V̇O2 max was After the first experimental visit, subjects were allocated in
measured using an electronically braked cycle ergometer a randomised, double blind manner to two experimental
(Lode NV Instrumenten, Groningen, the Netherlands) treatment groups. One group (n = 7) was instructed


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966 B. T. Wall and others J Physiol 589.4

to consume 700 ml of a solution containing 80 g of and long-chain acylcarnitine using the radioenzymatic
orange-flavoured CHO polymer (Vitargo; Swecarb AB, method described previously by Cederblad (Cederblad
Stockholm, Sweden) on two occasions each day for et al. 1990). Muscle ATP, phosphocreatine (PCr), free
168 days (Control), whilst the remaining group consumed creatine, lactate and glycogen were also determined
80 g of orange-flavoured CHO polymer containing 2.0 g on freeze-dried muscle using the spectrophotometric
of L-carnitine tartrate (1.36 g of L-carnitine; CarnipureTM , method of Harris (Harris et al. 1974). Muscle TC was
Lonza Group Ltd, Basel, Switzerland) in the same volume calculated as the sum of the three carnitine moieties,
of solution and at the same frequency (Carnitine). and was normalised for the highest total creatine content
Volunteers were instructed to ingest the first supplement from each individual’s three biopsies of that visit, a
at breakfast time and the second 4 h later. This feeding procedure routinely carried out to minimise variability
protocol was based upon a regimen we have previously from non-muscle constituents (Stephens et al. 2006a,b).
shown to increase whole-body carnitine retention over Muscle total creatine content was calculated as the
a 14 day period (Stephens et al. 2007). Volunteers were sum of free creatine and PCr. Approximately 10 mg
informed of the caloric content of the drinks (∼600 of the ‘wet’ muscle was used to determine PDCa,
calories per day) and advised to replace their customary expressed as the rate of acetyl-CoA formation (mmol
CHO supplement with the prescribed supplement and/or min−1 (kg wet muscle)−1 at 37◦ C) using methodology
amend their diet accordingly to try and avoid weight described previously by Constantin-Teodosiu et al.
gain. Volunteers were requested to record any side (1991b). In addition, maximal citrate synthase activity
effects associated with supplementation over the 24 week was determined spectrophotometrically on whole muscle
protocol. None were reported by either group. homogenates based on the methods of Opie & Newsholme
(1967); Zammit & Newsholme (1976) and expressed as
mmol min−1 (kg wet muscle)−1 .
Sample collection and analysis
On each experimental study day, venous blood
samples were collected whilst subjects rested in a Statistical analysis
semi-supine position. Following collection, blood glucose
concentrations were determined immediately using A two-way ANOVA for repeated measures (time and
an autoanalyser (YSI 2300 STATplus, Yellow Springs treatment effects) was performed to detect differences
Instruments, Yellow Springs, OH, USA). Two millilitres within and between treatment groups separately for the
of each basal resting blood sample was collected into three conditions (rest, 50% V̇O2 max and 80% V̇O2 max ). When
lithium heparin containers, and following centrifugation a significant time or treatment effect was observed a
(22,000 RCF at +4◦ C for 2 min) the plasma was snap one-way ANOVA or t test was performed, respectively,
frozen in liquid nitrogen and stored at −80◦ C until used to locate individual differences. Statistical significance was
to determine plasma TC concentration using a radio- declared at P < 0.05. All the values presented in text, tables
enzymatic assay (Cederblad et al. 1982). Finally, a further and figures represent mean ± the standard error of the
2 ml of each basal resting blood sample was allowed to mean (S.E.M.).
clot and following centrifugation (1,400 RCF at +4◦ C for
10 min) the serum was stored frozen at −80◦ C until used
to determine insulin concentration using a commercially
available radioimmunoassay kit (Coat-a-Count Insulin, Results
Diagnostics Products Corporation, Los Angeles, CA,
Subject characteristics
USA).
On each experimental visit, muscle biopsy samples Subject characteristics are displayed in Table 1. Body mass
were obtained from the vastus lateralis muscle at rest and was not different between groups before supplementation.
within 5 s of the end of exercise at 50% and 80% V̇O2 max However, there was a 2.4 kg increase in body mass
(whilst subjects were seated on the cycle ergometer) using from basal in the Control group after 12 weeks of
the percutaneous needle biopsy technique (Bergström, supplementation (P < 0.01), which remained elevated
1975). Muscle samples were immediately snap frozen in after 24 weeks (P < 0.05). The Carnitine group showed no
liquid nitrogen after removal from the limb. One portion change in body mass over the course of the study. Fasting
of each biopsy sample was freeze dried and stored at venous blood glucose and serum insulin concentrations
−80◦ C, whilst the remainder was stored ‘wet’ in liquid at baseline were not different between groups and did
nitrogen. Freeze-dried muscle was dissected free of visible not change throughout the study (Table 1). Fasting
blood and connective tissue, powdered and used for the plasma TC concentration was also not different between
determination of muscle free carnitine, acetylcarnitine groups before supplementation. However, plasma TC


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J Physiol 589.4 Muscle carnitine loading and fuel utilisation 967

Table 1. Subject characteristics before (0) and 12 and 24 weeks after twice daily oral ingestion of either 80 g of carbohydrate
(Control; n = 7) or 80 g of carbohydrate containing 2 g L-carnitine tartrate (Carnitine; n = 7)

0 12 24

Control Carnitine Control Carnitine Control Carnitine

Age (years) 24.6 ± 2.0 27.1 ± 2.2 — — — —

Height (cm) 181.4 ± 2.5 176.2 ± 1.4 — — — —
Body mass (kg) 73.1 ± 3.7 74.2 ± 2.5 75.5 ± 3.7 †† 73.9 ± 2.5 75.8 ± 4.3 † 74.4 ± 2.3
BMI (kg m−2 ) 22.2 ± 0.7 23.9 ± 0.9 22.9 ± 0.7 23.8 ± 0.8 23.0 + 0.9 24.0 ± 0.8
V̇O2 max (ml kg−1 min−1 ) 50 ± 2.6 54 ± 2.2 — — 51 ± 2.7 56 ± 2.5
Fasting blood glucose (mmol l−1 ) 4.1 ± 0.1 4.3 ± 0.1 4.2 ± 0.1 4.3 ± 0.1 4.1 ± 0.1 4.4 ± 0.1
Fasting serum insulin (mU l−1 ) 10 ± 0.4 10 ± 0.4 11 ± 0.1 10 ± 0.4 10 ± 0.4 11 ± 0.4
Fasting plasma carnitine (μmol l−1 ) 43 ± 2.5 44 ± 4.2 38 ± 3.3 52 ± 4.0∗ 41 ± 3.6 54 ± 3.3∗
All values are means ± S.E.M. Significantly different from Control: ∗ P < 0.05. Significantly different from before supplementation
(0): †P < 0.05, ††P < 0.01.

concentration in the Carnitine group was greater after However, after 24 weeks muscle TC content was 30%
12 and 24 weeks of supplementation when compared greater in the Carnitine group compared to Control
to the Control group (P < 0.05; Table 1). Perceived (P < 0.05), which represented a 21% increase from base-
exertion during exercise at 50% V̇O2 max did not differ line in the Carnitine group (P < 0.05).
between groups on any visit. The same was also
true during exercise at 80% V̇O2 max before and after
12 weeks of supplementation. However, after 24 weeks
of supplementation perceived exertion was lower in the Skeletal muscle metabolites
Carnitine group when compared to baseline (14.0 vs. 15.0, Absolute muscle metabolite values at rest and during
respectively; P < 0.05) and Control at 24 weeks (14.0 vs. exercise are presented in Table 2. From similar resting
16.2, respectively; P < 0.05). values, muscle PCr, glycogen, lactate, acetylcarnitine and
free carnitine content changed by a similar magnitude
during exercise at 50 and 80% V̇O2 max before and after
12 weeks of supplementation in Control and Carnitine
Skeletal muscle total carnitine content
groups. However, following 24 weeks of supplementation
Resting muscle TC content over the course of the study there was a trend (P = 0.09) for resting free carnitine
is shown in Fig. 1. There was no difference between or content to be 30% greater in the Carnitine group
within groups before or after 12 weeks of supplementation. compared to Control, and there was a significant difference

Figure 1
Total skeletal muscle carnitine content (calculated as the
mean of 3 biopsies taken from each individual during a
given visit) before (0) and 12 and 24 weeks after twice
daily oral ingestion of either 80 g of carbohydrate
(Control; n = 7) or 80 g of carbohydrate containing 2 g
L-carnitine tartrate (Carnitine; n = 7). All values are
means ± S.E.M.). Significantly different from Control:
∗ P < 0.05. Significantly different from before

supplementation (0): †P < 0.05.


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968 B. T. Wall and others J Physiol 589.4

Table 2. Skeletal muscle metabolites at rest and following 30 min of exercise at 50 and 80% V̇O2 max before (0) and 12
and 24 weeks after twice daily oral ingestion of either 80 g of carbohydrate (Control; n = 7) or 80 g of carbohydrate
containing 2 g L-carnitine tartrate (Carnitine; n = 7)

Rest 50% V̇O2 max 80% V̇O2 max

Control Carnitine Control Carnitine Control Carnitine

0 PCr 79.3 ± 8.6 90.0 ± 5.2 71.0 ± 8.0 64.8 ± 12.2 41.9 ± 5.2 38.1 ± 5.3
PCr/ATP ratio 3.5 ± 0.4 3.6 ± 0.2 3.1 ± 0.1 2.9 ± 0.3 1.6 ± 0.2 1.4 ± 0.2
Glycogen 430.2 ± 29.2 436.3 ± 20.5 380.7 ± 28.4 386.4 ± 10.1 235.2 ± 29.8 260.5 ± 22.7
Lactate 3.7 ± 1.4 3.0 ± 0.8 7.1 ± 2.4 7.5 ± 2.5 29.0 ± 4.7 27.5 ± 5.5
Acetylcarnitine 2.6 ± 0.4 2.5 ± 0.6 6.7 ± 0.8 8.1 ± 1.6 15.8 ± 0.8 17.4 ± 0.9
Free carnitine 17.9 ± 1.8 18.0 ± 1.8 14.0 ± 1.4 14.5 ± 1.5 9.4 ± 1.3 5.1 ± 0.9
Acyl-carnitine 0.9 ± 0.1 0.9 ± 0.1 0.8 ± 0.1 1.0 ± 0.1 1.3 ± 0.1 1.0 ± 0.1
12 PCr 87.8 ± 4.5 88.7 ± 5.8 63.6 ± 10.6 69.5 ± 6.3 47.9 ± 5.9 51.9 ± 8.6
PCr/ATP ratio 3.6 ± 0.2 4.1 ± 0.5 3.1 ± 0.3 2.8 ± 0.2 1.8 ± 0.3 2.0 ± 0.3
Glycogen 441.9 ± 34.0 393.2 ± 10.0 384.5 ± 40.4 346.4 ± 15.8 206.0 26.8 181.6 ± 17.6
Lactate 4.5 ± 0.6 3.2 ± 0.5 7.9 ± 2.3 5.5 ± 0.9 37.9 ± 5.0 32.0 ± 5.8
Acetylcarnitine 3.2 ± 0.6 4.4 ± 1.1 7.8 ± 1.7 7.0 ± 1.1 12.6 ± 1.3 15.6 ± 2.0
Free carnitine 16.2 ± 1.9 19.5 ± 2.0 12.7 ± 1.5 15.8 ± 1.3 7.9 ± 1.0 6.5 ± 1.0
Acyl-carnitine 0.7 ± 0.1 0.9 ± 0.2 0.9 ± 0.1 0.8 ± 0.1 0.8 ± 0.1 1.6 ± 0.4
24 PCr 70.3 ± 9.6 83.5 ± 9.0 70.3 ± 5.0 68.4 ± 13.0 33.3 ± 6.5 48.6 ± 6.3
PCr/ATP ratio 3.7 ± 0.1 3.4 ± 0.3 2.5 ± 0.4 3.0 ± 0.3 1.3 ± 0.2 2.7 ± 0.3∗†
Glycogen 386.4 ± 33.8 467.6 ± 24.8 326.1 ± 33.9 440.7 ± 24.1∗ 146.8 ± 17.4 251.7 ± 37.7∗
Lactate 4.4 ± 0.8 4.5 ± 1.0 7.7 ± 1.2 5.5 ± 0.6 44.4 ± 6.9 25.0 ± 4.1∗
Acetylcarnitine 2.8 ± 0.7 2.7 ± 0.8 7.7 ± 1.7 6.7 ± 1.5 15.8 ± 1.4 18.4 ± 1.7
Free carnitine 15.9 ± 1.6 20.7 ± 2.2 11.0 ± 1.3 19.6 ± 2.4∗∗† 5.4 ± 0.7 8.8 ± 1.7
Acyl-carnitine 0.9 ± 0.2 0.8 ± 0.1 0.7 ± 0.1 1.0 ± 0.2 0.9 ± 0.1 1.2 ± 0.4
All values are means ± S.E.M. and expressed as mmol (kg dry muscle)−1 . Significantly different from Control: ∗ P < 0.05,
∗∗ P < 0.01. Significantly different from before supplementation (0): †P < 0.05.

between groups in the metabolic response to both low (P < 0.05) and baseline (P < 0.05) following exercise at
and high intensity exercise. Following exercise at 50% 80% V̇O2 max .
V̇O2 max , muscle glycogen content was 35% greater in
the Carnitine group compared to Control (P < 0.05), Muscle PDCa
which equated to 55% less glycogen being utilised during
exercise (P < 0.05; Fig. 2A), and free carnitine was 78% Muscle pyruvate dehydrogenase activation status (PDCa)
greater in the Carnitine group when compared to Control following exercise is shown in Fig. 2C. Resting muscle
(P < 0.01). Following exercise at 80% V̇O2 max , muscle PDCa was not different between treatment groups
glycogen content was 71% greater in the Carnitine group at any time-point, being maintained at ∼0.4 mmol
compared to Control; however, this was attributable to acetyl-CoA min−1 (kg wet muscle)−1 . Similarly, muscle
the reduction in glycogen utilisation during the preceding PDCa following exercise at 50% V̇O2 max was not different
exercise at 50% V̇O2 max (see above), and accordingly there between treatment groups at baseline and 12 weeks;
was no difference between groups in glycogen utilisation however, at 24 weeks PDCa was 31% lower than baseline in
during exercise at 80% V̇O2 max (Fig. 2A). However, muscle the Carnitine group (P < 0.05). PDCa following exercise
lactate content was 44% lower in the Carnitine group at 80% V̇O2 max was not different between treatment groups
compared to Control (P < 0.05) following exercise at at baseline or after 12 weeks, but was 38% greater in the
80% V̇O2 max , which translated into a marked reduction Carnitine group at 24 weeks when compared with Control
in muscle lactate accumulation during exercise (P < 0.05, (P < 0.05).
Fig. 2B) and was accompanied by a trend (P < 0.10) for
muscle acetylcarnitine and free carnitine content to be Muscle citrate synthase activity
greater in the Carnitine group when compared to Control
(16% and 63%, respectively). In addition, after 24 weeks Muscle citrate synthase activity was not different between
of supplementation, the muscle PCr/ATP ratio in the Control or Carnitine groups at baseline (5.6 ± 0.9 and
Carnitine group was significantly greater than Control 5.0 ± 0.4 mmol min−1 (kg wet muscle)−1 , respectively)


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J Physiol 589.4 Muscle carnitine loading and fuel utilisation 969

or after 24 weeks of supplementation (5.4 ± 0.1 and different between groups before or after 12 weeks of
5.9 ± 0.7 mmol min−1 (kg wet muscle)−1 , respectively), supplementation. However, after 24 weeks work output
and there were also no differences over time. was 35% greater in the Carnitine group compared to
Control (P < 0.05), which represented an 11% increase
from baseline (P < 0.05).
Exercise performance
Work output (kJ) achieved in the exercise performance
test is presented in Fig. 3. Performance was not Discussion
Despite over 30 years of research demonstrating the
fundamental role of carnitine in regulating muscle fuel use,
attempts to increase skeletal muscle TC content in humans
via L-carnitine feeding have been unsuccessful (Barnett
et al. 1994; Vukovich et al. 1994; Wächter et al. 2002).
The present study is the first to demonstrate that muscle
TC content can be increased by 21% in healthy human
volunteers when L-carnitine is ingested for 24 weeks in
combination with a CHO solution. Moreover, this increase
in TC content had a profound effect on muscle fuel
utilisation during exercise which was exercise intensity
dependent and consistent with the reported dual role of
carnitine in muscle fuel metabolism. Namely, during low
intensity exercise muscle glycogen utilisation was halved
(consistent with an increase in muscle lipid utilisation),
whereas during high intensity exercise muscle lactate
accumulation was substantially reduced and the muscle
PCr/ATP ratio was better maintained, which probably
resulted from the carnitine-mediated increase in PDC
activation and flux observed at this workload. Finally,
increasing skeletal muscle TC content was associated with
a 35% improvement in work output over Control, which
we propose resulted directly from the observed changes in
muscle fuel metabolism.
A major role of carnitine in skeletal muscle is as a sub-
strate for the CPT1-mediated translocation of fatty acids
into mitochondria for subsequent β-oxidation (Fritz &
McEwen, 1959; Fritz & Yue, 1963). We have previously
shown that a 15% increase in muscle TC content resulted in
the attenuation of insulin-induced increases in glycolytic
flux and PDCa in healthy, resting volunteers, as well as a
subsequent overnight increase in muscle glycogen storage.
This effect was attributed to a carnitine-mediated increase
in acetyl-CoA delivery from fat oxidation, which inhibited
PDCa and diverted glucose uptake from oxidation towards
storage, and therefore suggests that carnitine availability is
limiting to the CPT1 reaction under insulin-stimulated
conditions, even at rest (Stephens et al. 2006b). We
Figure 2 therefore hypothesised that during low intensity exercise
Skeletal muscle glycogen utilisation (A), lactate accumulation (B) and
in the present study, when glycolytic and PDC flux are well
pyruvate dehydrogenase complex activation status (C) during 30 min
of exercise at 50 and 80% V̇O2 max before (0) and 12 and 24 weeks matched, an increase in muscle free carnitine availability
after twice daily oral ingestion of either 80 g of carbohydrate would have a similar effect, i.e. it would augment muscle
(Control; n = 7) or 80 g of carbohydrate containing 2 g L-carnitine lipid oxidation thereby blunting PDCa and glycolytic
tartrate (Carnitine; n = 7). All values are means ± S.E.M. Significantly flux. Consistent with this hypothesis, we observed that
different from corresponding Control: ∗ P < 0.05. Significantly
the increase in muscle TC content after 24 weeks of
different from before supplementation (0): †P < 0.05.
supplementation was linked to a 55% reduction in


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970 B. T. Wall and others J Physiol 589.4

muscle glycogen utilisation during exercise at 50% V̇O2 max V̇O2 max in the Carnitine group, makes it highly unlikely
compared to Control. Furthermore, this was accompanied that an increase in mitochondrial content occurred over
by muscle free carnitine content being ∼80% greater and the 24 weeks of supplementation.
PDCa being 31% lower during exercise compared to before Another widely documented function of carnitine is as
supplementation, suggesting that a carnitine-mediated an acetyl group buffer during conditions of high glycolytic
increase in lipid-derived acetyl-CoA inhibited PDCa and PDC flux. During high intensity exercise, when acetyl
(Pettit et al. 1975) and thereby reduced muscle CHO flux, group production by the PDC reaction is in excess of its
which is consistent with The Randle Cycle (Randle et al. utilisation by the TCA cycle, free carnitine buffers against
1963). Free carnitine availability has been suggested to acetyl-CoA accumulation by forming acetylcarnitine in a
limit muscle fat oxidation in vivo in humans during intense reaction catalysed by carnitine acetyl transferase (CAT),
exercise when its concentration declines below 6 mmol (kg thereby ensuring a viable supply of free CoASH to sustain
dry muscle)−1 (∼2 mmol (l intracellular water)−1 ) (van TCA cycle flux (Childress & Sacktor, 1966; Harris et al.
Loon et al. 2001). However, during exercise at 50% V̇O2 max 1987; Constantin-Teodosiu et al. 1991a). In the context
in the present study muscle free carnitine concentration of this, another major finding of the present study was
was 11 mmol (kg dry muscle)−1 (∼3.5 mmol (l intra- the marked reduction in muscle lactate accumulation
cellular water)−1 ), which is above the value reported by during exercise at 80% V̇O2 max in the carnitine-loaded
van Loon et al. (2001) and well above the reported K m of state after 24 weeks of supplementation when compared
CPT1 for free carnitine (0.5 mmol l−1 ) (McGarry et al. to Control, an effect probably mediated by the greater
1983). Therefore, either the reported K m of carnitine PDCa (38%) and flux (as evidenced by the 16% greater
for CPT1, generated via in vitro experiments (McGarry acetylcarnitine content) observed compared to Control.
et al. 1983) is not transferable to the in vivo situation While it is clear that after 24 weeks muscle lactate did
or, alternatively, although the cellular carnitine pool is not accumulate in the Carnitine group to any lesser of
thought to be predominantly (90%) cytosolic (Zammit, an extent than seen at baseline, it is important to note
1999), the availability of free carnitine to CPT1 is markedly that the absence of a change occurred in the face of
lower than suggested from determination of free carnitine increased glycogenolysis in both groups, which resulted
in whole muscle homogenates. An explanation for this may in an increased lactate accumulation in the Control group
be that the known catalytic site of CPT1 is located within only, and is explained by the carnitine-mediated increase
the contact sites of the outer mitochondrial membrane and in PDCa and flux in the Carnitine group. Furthermore, the
therefore not entirely available to the cytosolic carnitine magnitude of cellular energy disturbance (as indicated by
pool. An increase in mitochondrial content over the PCr/ATP ratio) was significantly reduced during exercise
duration of the study could also explain the apparent at 80% V̇O2 max at 24 weeks in the Carnitine group when
increase in fat oxidation and glycogen sparing observed compared to baseline and Control at 24 weeks. In keeping
in the Carnitine group during exercise at 50% V̇O2 max after with this observation, we, and others, have previously
24 weeks. However, if this was the case it would be expected reported that inertia in mitochondrial ATP production
that citrate synthase activity and/or V̇O2 max would have also during the rest to exercise transition is at least partly
increased in this group, which was not observed. These limited by PDC activation and flux, resulting in increased
observations, together with the finding that there was anaerobic ATP generation (Timmons et al. 1997, 1998;
no evidence of glycogen sparing during exercise at 80% Howlett et al. 1999; Roberts et al. 2002, 2005).

Figure 3
Work output generated during a 30 min ‘all-out’
exercise performance test performed immediately
following 30 min of exercise at 50 and 80% V̇O2 max
before (0) and 12 and 24 weeks after twice daily oral
ingestion of either 80 g of carbohydrate (Control;
n = 7) or 80 g of carbohydrate containing 2 g
L-carnitine tartrate (Carnitine; n = 7). All values are
means ± S.E.M. Significantly different from Control:
∗ P < 0.05. Significantly different from before

supplementation (0): †P < 0.05.


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J Physiol 589.4 Muscle carnitine loading and fuel utilisation 971

Pyruvate dehydrogenase activation status is principally et al. 1993). Furthermore, Coyle (1995) concluded that
regulated by a covalent mechanism of competing pyruvate the ability to maintain a high steady-state V̇O2 with low
dehydrogenase kinase (PDK) and pyruvate dehydrogenase muscle lactate content is a prerequisite for enhanced
phosphatases (PDP), which inactivate and activate the endurance exercise performance in elite athletes. Indeed,
PDC, respectively. Pyruvate dehydrogenase kinase and muscle lactic acidosis has been suggested as a primary
PDP are themselves subject to metabolic regulation, cause of fatigue during high-intensity exercise (Sahlin,
and Ca2+ has been suggested as the principal metabolic 1992), hence the efforts to increase muscle buffering
activator of PDC during exercise by stimulating PDP capacity by β-alanine feeding (Hill et al. 2007) or establish
(Constantin-Teodosiu et al. 2004). Considering that pre-exercise metabolic alkalosis by sodium bicarbonate
subjects in the present study exercised at the same work ingestion (Wilkes et al. 1983; McKenzie et al. 1986; Bird
intensity (80% V̇O2 max ) during each visit, it can be assumed et al. 1995) to improve high intensity exercise performance
that the increase in cellular Ca2+ concentration was equal in humans. Finally, given that muscle glycogen content was
between visits and accordingly a similar stimulatory effect 147 mmol (kg dry muscle) −1 following exercise at 80%
on the PDC was exerted regardless of skeletal muscle TC V̇O2 max in the Control group, it is possible that glycogen
content. However, PDC activation is also regulated by availability may have limited performance in this group
end-product inhibition, primarily by an increase in the during the 30 min work output trial, which would not
acetyl-CoA/CoASH ratio which stimulates PDK (Cooper have been the case in the Carnitine group where glycogen
et al. 1975; Pettit et al. 1975). Thus, as well as blunting was 250 mmol (kg dry muscle)−1 . It cannot be ruled out
acetyl-CoA accumulation during intense exercise and therefore that at least some of the positive effect of muscle
augmenting PDC flux, increased acetyl group buffering in carnitine loading on exercise performance was attributable
the Carnitine group may also have modulated a reduction to the glycogen sparing that occurred during exercise
in the acetyl-CoA/CoASH ratio, thereby explaining the at 50% V̇O2 max . Whether the beneficial effects of muscle
greater PDCa in the carnitine-supplemented group at 80% carnitine loading on high intensity exercise and exercise
V̇O2 max following 24 weeks of carnitine supplementation performance led to the better maintenance of body mass
compared with Control. in the face of 24 weeks of additional daily caloric intake
Given that the performance test used in this study when compared to control (i.e. via a regular increased
is reproducible (Jeukendrup et al. 1996; Stephens et al. energy expenditure during exercise training) is an inter-
2008), and all the volunteers were recreational athletes esting notion, but cannot be determined from the present
familiar with intense exercise, a major finding of the study and remains to be explored.
present study has to be that the increase in muscle TC In summary, this is the first study to demonstrate
content after 24 weeks of supplementation resulted in that muscle carnitine content can be increased in
a 35% increase in work output compared to Control humans by dietary means and, perhaps more importantly,
(and an 11% increase from baseline). We, and others, that carnitine plays a dual role in skeletal muscle
have previously demonstrated that complete activation of fuel metabolism that is exercise intensity dependent.
PDC in the resting state, by pharmacological inhibition Specifically, we have shown that increasing muscle TC
of PDK, markedly reduced anaerobic energy production content spares muscle glycogen during low intensity
in canine and human skeletal muscle during subsequent exercise (consistent with an increase in muscle lipid
intense contraction (Timmons et al. 1997, 1998; Howlett utilisation), but during high intensity exercise results in
et al. 1999; Roberts et al. 2002, 2005), and resulted in a a better matching of glycolytic, PDC and mitochondrial
substantial improvement in muscle contractile function flux, thereby reducing muscle anaerobic ATP production.
(Timmons et al. 1997). It would appear therefore that the Furthermore, these metabolic changes resulted in positive
38% greater PDCa and associated flux during exercise effects on perception of effort and work output
at 80% V̇O2 max in the carnitine-loaded state in the using a validated exercise performance test. Collectively
present study, coupled with the reduction in muscle these findings have significant implications for athletic
lactate accumulation and lower perceived exertion during performance and pathophysiological conditions where fat
exercise compared with Control, positively impacted oxidation is impaired or anaerobic ATP production is
upon work output during the subsequent performance accelerated during exercise (Noland et al. 2009).
trial. Indeed, it is likely that these metabolic effects
observed at 80% V̇O2 max in the carnitine-loaded state
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intensity on muscle fuel utilisation in humans. J Physiol 536, The experiments in this paper were conducted in the School
295–304. of Biomedical Sciences, University of Nottingham. All authors
Vukovich M, Costill D & Fink W (1994). Carnitine approved the final version of the manuscript to be published
supplementation: effect on muscle carnitine and glycogen and all authors contributed to drafting the article and revising
content during exercise. Med Sci Sports Exerc 26, 1122–1129.
it critically for important intellectual content. All authors
Wächter S, Vogt M, Kreis R, Boesch C, Bigler P, Hoppeler H &
contributed to the conception and design, or analysis and inter-
Krähenbühl S (2002). Long-term administration of
pretation of the data in the manuscript.
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Wilkes D, Gledhill N & Smyth R (1983). Effect of acute induced Acknowledgements
metabolic alkalosis on 800-m racing time. Med Sci Sports
Exerc 15, 277–280. The authors would like to thank Mr Ryan Atkins for his assistance
Zammit V (1999). Carnitine acyltransferases: functional with the determination of citrate synthase activity, QinetiQ for
significance of subcellular distribution and membrane their sponsorship of this research and Energ8 Ltd for donating
topology. Prog Lipid Res 38, 199–224. the carbohydrate and L-carnitine supplements used in the study.


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