Denis
St.J O’Reilly1, Roger Carter2, Ewan Bell1,
1
Department of Clinical Biochemistry, Royal Infirmary, Glasgow G4 0SF
2
Department of Respiratory Medicine, Royal Infirmary, Glasgow G4 0SF
3
Department of Medicine, Royal Alexandra Hospital, Paisley PA2 9PN
4
Department of Clinical Biochemistry, Royal Hospital for Sick Children,
Yorkhill, Glasgow G3 8SJ
Key
Words:
Anaerobic Threshold, Exhaustion, McArdle’s Disease,
Correspondence
to: Dr Denis St.J O’Reilly
Department of Clinical Biochemistry
Glasgow Royal Infirmary
GLASGOW G4 0SF
SUMMARY
The
cardio-pulmonary and biochemical changes observed in a case of McArdle’s
disease, exercising with increasing work rates to exhaustion in the
“second-wind” phase of exercise are reported for the first time.
A work rate of 275-325 watts was achieved.
Venous blood lactate remained unchanged throughout.
The plasma ammonium level reached a plateau of approximately 400 mmol/l
at 100 watts. At a work rate
of 150-175 watts the ratio of O2 consumption to CO2
production increased, the inverse of an anaerobic threshold.
Maximal cardio-pulmonary responses were achieved at 200 watts.
During the final periods of exercise from 200 to 275/325 watts
pulmonary ventilation did not significantly change but there was a decrease in
the venous blood H+ concentration, and pO2 and in increase
in the pCO2. Creatine
supplementation at 25 g/day for five days did not improve exercise
performance.
INTRODUCTION
It
is 50 years since the initial description of McArdle’s disease and 40 years
since it was established that it was caused by a defect in the muscle
phosphorylase enzyme.1 Since
then the condition has been the subject of detailed study.
It has been demonstrated that intravenous infusions of glucose improve
exercise tolerance2 and the development of diabetes mellitus also
appears to ameliorate the condition.3
However, no practical treatment has been proven in a placebo controlled
trial to be effective.
A
feature of McArdles disease is that subjects suffer muscle cramp and exhaustion
on acute strenuous exercise. They
then experience a so-called “second-wind” which, if they persist, enables
them to continue to exercise without pain.1
Though unproven, the most plausible and generally accepted explanation
for the “second-wind” phenomenon, is that the myocytes switch from
intracellular sources to energy from free fatty acids derived from an increased
in muscle blood flow.1
Currently,
there is a lot of interest in the use of creatine,4 and other food
supplements5 to improve skeletal muscle performance.
There are data to suggest that supplementation with 20-25 g of
creatine daily for 5-6 days can improve muscle performance in acute strenuous
exercise.5 Muscle biopsy
data, in a study involving low muscle work rates, suggest that in McArdle’s
disease the phosphocreatine stores are rapidly depleted.6
The
aim of this study was to investigate if creatine supplementation improved the
exercise capacity of a subject with McArdle’s disease
SUBJECT
At
the time of the study, the subject was a 47 year old male: height 1.74 m, weight
89 kg and a non-smoker. Apart from
the symptoms of McArdle’s disease he had no symptoms or signs suggestive of
cardiac or pulmonary disease.
McArdle’s
disease was diagnosed at the age of 26 years.
On initial presentation his serum creatine kinase of 798 U/L and a
decrease in the venous plasma lactate from 0.73 mmol/L to 0.3 mmol/L was
observed, one minute after ischaemic forearm exercise test.
A skeletal muscle biopsy had a glycogen content of 3% wet weight
(reference range <1%) and a phosphorylase activity = 1.5 mmol
phosphate/g/minute in the presence of AMP (reported as approximately 3% of the
lowest normal control – Institute of Child Health, University of London, UK in
1977). No phosphorylase activity
was detected in skeletal muscle by histochemistry.
He has a lifelong history of severe muscle pain and exhaustion on sudden
moderate exercise.
When
the diagnosis was made he was advised to maintain an active life.
He exercises into the “second-wind” phase approximately twice weekly.
The study was instigated and designed by the subject.
Pulmonary
function was measured in a constant volume body plethysmograph (Sensormedics,
V6200 Autobox, California, USA) using the protocols established by the European
Respiratory Society.7 His
forced vital capacity (FVC) = 4.56 L (92% of predicted), FEV1 = 3.46
L (92% of predicted), the FEV1/FCV
% = 75% (101% of predicted) and a
maximum voluntary ventilation (MVV) = 129 L/ minute (105% of
predicted. The flow loop diagram
showed no evidence of airways obstruction.
He
followed his normal routine but ingested 25 g of creatine or 25 g of glucose
daily in four divided doses for five days prior to each period of study.
Supplementation with this amount of creatine for five days was chosen on
the basis of previous studies on healthy subjects who did not have McArdles
disease.5 The last dose,
6.25 g of creatine or 6.25 g of glucose was taken on the morning of
the study periods with a light breakfast of tea and cereal. The
subject fasted for the 4-5 hours before the periods of study.
The subject could distinguish the creatine from glucose on the basis of
taste and consistency. There was a
minimum of four weeks between each of the four studies.
Exercise
testing was carried out on an electrically braked bicycle-ergometer (Cardiokinetics
Ltd, Salford, UK) with the subject breathing through a low dead-space,
low-resistance, valve box which incorporated a flexible pneumotachograph (Flexiflow,
Morgan Medical, Kent, UK) in the inspiratory limb to measure tidal volume and
respiratory frequency. The oxygen (using fuel cell and zirconium analyser) and
carbon dioxide (infra-red spectrometry) fractional concentrations were measured
in mixed expired air (Benchmark Exercise System, Morgan Medical, Kent, UK).
To
minimise bias he was blindfolded while exercising so that he was unable to tell
from the surrounding instrumentation the intensity or duration of the exercise.
The
power demands were increased at two-minute intervals by 25 watts
increments. Exhaustion was defined at the point when he could no longer
maintain a pedalling speed of 60 revolutions/minute to sustain the power
requirements. He was not informed
when the power demands were increased but exhaustion was reached within 30
seconds of an incremental increase. The
power output maintained for the previous two minutes was defined as the exercise
limit. Only one experimenter (R.C.)
spoke to the subject during the periods of exercise to enable him to maintain
the appropriate pedalling speed.
Venous
blood was collected from an indwelling venous cannula in the anticubital fossa.
Lactate was measured enzymatically (Lactate PAP Kit bioMerieux, 69280
Marcy, l’Etoile, France). Plasma
ammonium was measured by bromophenol blue, glucose by the glucose oxidase
method, and potassium by ISE on a Kodak Ektachem 750 RC analyser using Vitros
chemistry products (Ortho Clinical Diagnostics Inc, Johnston & Johnston Co,
Rochester, New York, USA). Venous
blood hydrogen ion concentration, pO2 and pCO2 were
measured on a Corning 865 blood gas analyser (Chiron Diagnostics, Halstead, UK).
RESULTS
After five days of creatine supplementation the subject was able to achieve an exercise intensity of 325 watts and 300 watts and after five days of glucose 325 and 275 watts.
The
cardio-pulmonary responses to exercise are given in Figure 1.
The mean basal pulmonary ventilation = 7.5 L/minute, this increased
by 26.5 L/minute to 30.0 L/minute when the exercise intensity
increased to 100 watts. The
mean pulmonary ventilation increased by 27 L/minute to 61.0 L/minute
(47% of predicted MVV) when the exercise intensity increased from 100 to
200watts. Thereafter, the pulmonary
ventilation increased by only 3.9 L/minute to 64.9L/minute (50% of
predicted MVV) at exhaustion. The
mean heart rate also increased in a linear fashion from 65 to 152 beats/minute
(94% of predicted maximum) as the exercise increased to 200 watts it
increased slightly to a mean value of 163 beats/minute at exhaustion.
A
threshold was detected using the non-invasive method of Beaver et al9
from the ratio of the CO2 production and O2 consumption.
This was detected at 150 and 175 watts on creatine and at the same
exercise intensities on glucose. However,
in healthy subjects the change in the ratio occurs when CO2
production increases relative to O2 consumption (ie, the anaerobic
threshold).8 In the
subject, the change signalled an increase in O2 consumption relative
to CO2 production (ie, the inverse of an anaerobic threshold).
Subsequently, an increasing work rate was associated with an O2
consumption which was not matched by a corresponding increase in CO2
production.
Oxygen
consumption and CO2 production increased throughout the period of
exercise. At exhaustion the forearm
venous blood pO2 decreased, the PCO2 increased and the hydrogen ion
concentration decreased. The plasma
potassium and glucose concentrations were at there highest at 100 watts
and slowly decreased over the subsequent 14-18 minutes of exercise (Table
1). The venous plasma lactate
concentration did not significantly change during exercise.
The mean±SD
= 0.85±0.07 mmol/L (CV = 8.2%, n = 18) during
exercise.
The
plasma ammonium concentration rapidly increased to approximately 400 mmol/L
at the end of the period of exercising at 100 watts. The plasma ammonium
concentrations were very variable on placebo or creatine (Table
1).
The
study was not designed to look at the recovery period but some data was
collected after two periods of exercise (Table 1). During early recovery the pCO2 continued to
increase and the pO2 decreased.
In one study (B) the ammonium concentration at 60 minutes = 113 mmol/L
and at 120 minutes = 22 mmol/L.
Cardio-pulmonary data were not collected.
DISCUSSION
The
biochemical and cardio-pulmonary changes that occur in exercise of increasing
intensity to exhaustion in the “second-wind” phase have not been previously
reported. The data presented
indicate that the subject, after a slow increase, achieved a work rate
equivalent to those obtained by healthy controls.
At a dose of 25g/day for five days creatine had no measurable effect on
exercise capacity.
The
rapid increase in plasma ammonium on exercising to 100watts is compatible with
previously reported studies.9 It
has been suggested that the increase in ammonium is either a mediator or marker
of the metabolic events causing the increased heart rate and/or fatigue.9 Our data would not support these hypotheses.
The plasma ammonium reached a plateau after 100 watts with only
modest increases thereafter, while the cardio-pulmonary responses increased in a
linear fashion to a work rate of approximately 200 watts.
He did not experience muscle pain or cramp during the “second-wind”
phase of the exercise.
The
maximal cardio-pulmonary responses were achieved at a work rate of approximately
200 watts. The plateau in
cardio-pulmonary responses leading up to exhaustion, despite some additional
respiratory reserve as measured by his maximum voluntary ventilation.
In health on strenuous exercise as lactate production increases, the
accompanying increase in H+ production is primarily buffered by
bicarbonate, with each mmol of lactate generating 22 ml of CO2.9
This increase in CO2 production is detected as the anaerobic
threshold. However, in McArdles
disease, lactate production does not increase and, in this subject, venous
hydrogen ion concentration decreased as the intensity of exercise increased.
This would explain the “inverse” anaerobic threshold observed in this
subject and the absence of an increase in pulmonary ventilation leading up to
exhaustion.
DECLARATION
D
St.J O’Reilly was the subject, conceived of the study and wrote the first and
final version of the manuscript. The
study was designed and planned by D St.J O’Reilly,
R Carter (who collected and analysed the cardio-pulmonary data) J Hinnie
and P Galloway. E Bell
and P Galloway coordinated the biochemical analyses.
All authors contributed to writing the manuscript.
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