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Spontaneous "Second Wind" and Glucose-Induced Second "Second Wind" in McArdle Disease
Oxidative Mechanisms
Ronald G. Haller, MD;
John Vissing, MD, PhD
Arch Neurol. 2002;59:1395-1402.
ABSTRACT
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Background Blocked glycogen breakdown in McArdle disease impairs oxidative as well
as anaerobic metabolism, but the contribution of impaired oxidative phosphorylation
to everyday symptoms of McArdle disease remains poorly defined.
Objective To evaluate the oxidative implications of the spontaneous second wind
and variables that influence the development of this typical feature of McArdle
disease.
Design Assessment of exercise and oxidative capacity ( O2)
before and after the spontaneous "second wind" and with a glucose infusion
after a spontaneous second wind.
Patients Eight patients with complete myophosphorylase deficiency and 1 unique
patient with 3% of normal myophosphorylase activity.
Main Outcome Measures Work capacity, O2, heart rate, cardiac output.
Results All patients with complete myophosphorylase deficiency (1) had low peak O2 (mean ± SD, 13.0 ± 2.0 mL · kg-1·
min-1) in the first 6 to 8 minutes of exercise; (2) achieved
a spontaneous second wind with increased exercise capacity between 8 and 12
minutes of exercise due to a more than 25% increase in peak O2 (16.5 ± 3.1 mL · kg-1· min-1); and (3) with glucose infusion after a spontaneous second
wind, experienced a further more than 20% increase in oxidative capacity (O2, 19.9 ± 3.9 mL · kg-1· min-1). In the patient with residual myophosphorylase, O2 (22.2 mL · kg-1· min-1)
in the first 6 to 8 minutes of exercise was approximately 2-fold higher than
the mean of patients lacking myophosphorylase, and no significant improvement
in exercise and oxidative capacity accompanied prolonged exercise or glucose
infusion.
Conclusions First, the spontaneous second wind and the glucose-induced second second
wind in McArdle disease are due to substrate-dependent increases in muscle
oxidative capacity. Second, by providing glycogen-derived pyruvate, a small
amount of residual myophosphorylase activity normalizes the oxidative deficit
of complete myophosphorylase deficiency and virtually eliminates the spontaneous
second wind and glucose-induced second second wind.
INTRODUCTION
ABSENCE OF the muscle form of glycogen phosphorylase (myophosphorylase
deficiency or McArdle disease) blocks the breakdown of intramuscular glycogen.
The major energetic consequence traditionally has been considered to be an
absence of anaerobic glycogenolysis (glycogen metabolized to lactic acid),
and the clinical observation that ischemic exercise produces muscle contractures
and rhabdomyolysis confirms the role of impaired anaerobic production of adenosine
triphosphate (substrate-level phosphorylation) in the generation of these
typical symptoms of McArdle disease. Blocked glycogen breakdown also has been
shown to impair muscle aerobic metabolism (glycogen metabolized to carbon
dioxide and water).1-3
However, the clinical correlates of impaired oxidative metabolism are not
well defined.
A typical feature of McArdle disease that is likely attributable to
glycogen-limited oxidative metabolism is the "second wind" phenomenon. As
first described by Pearson and coworkers,4
the second wind denotes a sudden, marked improvement in exercise capacity
in which exercise that previously produced muscle fatigue, tachycardia, and
often breathlessness becomes easily tolerated.4-7
Pearson et al identified 2 varieties of second wind—one that could be
induced by the infusion of carbohydrate or lipid fuels and one that occurred
spontaneously.4 Evidence has now accumulated
that the second wind that can be induced in the laboratory by infusing various
fuels is due to an increase in muscle capacity for oxidative phosphorylation.1-2,8 However, no studies
have directly addressed the oxidative implications of the more clinically
relevant spontaneous second wind or variables that might influence the occurrence
of this classic clinical feature of McArdle disease.
We investigated the hypothesis that the spontaneous second wind is a
direct consequence of restricted oxidative fuel availability when glycogenolysis
is blocked, and represents a transition from low to a higher capacity for
oxidative phosphorylation as the availability of extramuscular fuels increases.
Furthermore, we investigated whether oxidative metabolism remains limited
by fuel availability after the development of a spontaneous second wind by
assessing the effect of a glucose infusion on oxidative capacity. Finally,
we examined whether residual muscle phosphorylase activity would augment muscle
oxidative capacity and, by reducing muscle dependence on blood-borne fuels,
blunt or eliminate the spontaneous second wind.
SUBJECTS AND METHODS
SUBJECTS
We studied 9 patients: 2 brothers, aged 39 and 42 years, and 7 additional,
unrelated patients, 3 men aged 50, 37, and 27 years and 4 women aged 42, 40,
33, and 29 years. Eight of the patients had complete myophosphorylase deficiency.
One patient (a 37-year-old man) had 3% of control values for biochemically
determined myophosphorylase activity. This patient is unique among more than
40 patients with McArdle disease whom we have personally examined both with
respect to the residual enzyme activity and in that venous effluent lactate
in this patient approximately doubled after ischemic forearm exercise. This
is in contrast to the complete absence of lactate production in typical patients
with McArdle disease, including the 8 patients in this report, and to a 4-
to 5-fold lactate increase in control subjects.9
This patient experienced premature fatigue and sometimes cramps with intense
exercise such as weightlifting and rope climbing, and had experienced an episode
of myoglobinuria and renal failure triggered by weightlifting to "get in shape,"
but tolerated moderate exercise such as walking at a brisk pace without fatigue.
Screening for the 2 most common myophosphorylase gene mutations (R49X and
G204S) in 8 of our patients showed that the 2 brothers and the 42-year-old
woman were homozygous and 3 additional patients were heterozygous for the
R49X mutation.10 Two were heterozygous for
the G204S mutation, including the patient with residual myophosphorylase activity.
The mutations in the remaining alleles were not identified. One patient was
unavailable for genetic testing.
The research protocol was approved by the institutional review board
of The University of Texas Southwestern Medical Center at Dallas. Each subject's
consent was obtained according to the Declaration of Helsinki.
EXERCISE
Patients were tested after an overnight fast. Intravenous catheters
were placed for blood sampling and, in the opposite arm, for infusion of glucose.
Subjects cycled continuously (CPE 2000; Medical Graphics Corp, St Paul, Minn)
for about 40 minutes. Initial work capacity was determined in the first 6
to 8 minutes of exercise. Then the workload was reduced for 5 to 10 minutes,
similar to the strategy patients use to facilitate achieving a spontaneous
second wind.11 The workload was again progressively
increased to determine peak work capacity at approximately minute 25 of exercise.
Immediately thereafter, 50 mL of 50% glucose was infused during a period of
1 to 2 minutes, followed by a continuous, 6-mL/min infusion of 10% glucose
for the duration of exercise. The exercise workload was maintained or transiently
reduced and then increased to assess peak work capacity at approximately 40
minutes of exercise. Because of substantial differences in the exercise responses
of the patient with residual myophosphorylase activity compared with typical
patients with McArdle disease, 3 separate exercise tests were performed during
a span of 24 months in this patient. Since there were only minor and inconsistent
differences between these tests, results for this patient are presented as
the mean of the 3 tests.
PHYSIOLOGICAL MONITORING
Heart rate was monitored continuously with a 12-lead electrocardiogram.
Gas exchange and cardiac output were measured at rest and during peak exercise
within the initial 6 to 8 minutes of exercise, after patients achieved a spontaneous
second wind, and after glucose infusion following the spontaneous second wind.
Ventilation was measured by means of ventilation bags (Douglas bags; Warren
E. Collins Inc, Baintree, Mass) and a spirometer (Tissot; Warren E. Collins
Inc); fractions of oxygen, carbon dioxide, and nitrogen in expired air were
determined with a mass spectrometer (Marquette 1100; GE Marquette, Milwaukee,
Wis); and oxygen uptake (O2), carbon dioxide production,
ventilatory equivalent for oxygen (ventilation divided by O2),
and respiratory exchange ratio (carbon dioxide production divided by O2) were calculated. Cardiac output was measured with acetylene rebreathing
in which the rate of disappearance of acetylene from a rebreathing bag is
proportional to pulmonary blood flow and cardiac output ( ).12 Systemic arteriovenous (AV) oxygen difference was
calculated from the Fick equation: O2 = cardiac output x
systemic AV oxygen difference. The increase in cardiac output ( )
relative to the increase in O2 (O2)
from rest to exercise was determined as the ratio /O2.
ASSAYS
Blood was obtained from a forearm vein at rest and during peak exercise
under initial, spontaneous second wind, and glucose infusion conditions. Whole-blood
samples were assayed for lactate and glucose by means of a commercially available
analyzer (YSI Incorporated, Yellow Springs, Ohio) and for free fatty acids
by means of a commercially available kit (Wako Chemicals GmbH, Neuss, Germany).
STATISTICS
The statistical significance of differences among resting, fasting,
second wind, and glucose conditions was evaluated by means of a Newman-Keuls
multiple comparisons test or a paired t test. Differences
were considered significant when P .05. Data are
reported as mean ± SD, unless otherwise indicated.
RESULTS
WORK CAPACITY DURING CONTINUOUS EXERCISE
A typical exercise response in a patient with complete myophosphorylase
deficiency is indicated in Figure 1.
Peak work at 7 minutes of exercise was 30 W with a heart rate of 172 beats/min.
As the workload was reduced, between minutes 8 and 10, the patient experienced
the onset of a second wind marked by decreasing exercise effort and a falling
heart rate. By minute 12, the 30-W workload that had caused fatigue and tachycardia
was easily tolerated, and the heart rate had fallen to 126 beats/min. The
heart rate was stable while the workload remained at 30 W for the next 5 minutes;
then the workload was able to be increased to 55 W, corresponding to a heart
rate of 171 beats/min, in minute 22 of exercise. Then, 50 mL of 50% dextrose
was infused while the workload remained at 55 W. Shortly after the glucose
bolus, the patient experienced a second second wind associated with decreased
effort and a fall in heart rate to 147 beats/min during approximately 3 minutes.
The heart rate was stable for the next 5 minutes. Then the workload again
was able to be increased to a new peak of 70 W, corresponding to a heart rate
of 168 beats/min at minute 34 of exercise.
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Figure 1. Heart rate during continuous cycle
exercise in a 29-year-old woman with complete myophosphorylase deficiency
under conditions corresponding to initial, spontaneous second wind, and glucose
conditions, as described in the text.
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All 8 patients with complete myophosphorylase deficiency had a similar
response (Figure 2). Peak work rose
from 39 ± 17 W at 7 ± 1 minutes of exercise to 57 ± 21
W (P<.001) after achieving a second wind. After
glucose infusion, work capacity further increased to 74 ± 28 W (P = .002). The patient with residual myophosphorylase cycled
at 100 W in the first 7 minutes of exercise, a level 2.5-fold higher than
the mean of patients with complete myophosphorylase deficiency and, in contrast
to all of the other patients, did not demonstrate substantial improvement
in exercise capacity as exercise was prolonged or after glucose infusion (Figure 2 and Figure 3).
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Figure 2. Peak workload (A) and corresponding
peak heart rates (B) determined at 3 points during continuous cycle exercise:
"initial" denotes peak work capacity determined at 7 ± 1 minutes of
exercise, mean ± SD (before the onset of the second wind); "second
wind" corresponds to peak work capacity determined after the onset of a spontaneous
second wind, at 23 ± 2 minutes of exercise; and "glucose" denotes peak
exercise determined after glucose infusion, at 39 ± 3 minutes of exercise.
Symbols correspond to individual patients; squares represent men, and circles
and diamond represent women with typical McArdle disease with no residual
myophosphorylase activity. The triangles represent results from the patient
with partial myophosphorylase deficiency. Note the substantially higher work
capacity in this patient compared with the other patients with McArdle disease
in the first 6 to 8 minutes of exercise.
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Figure 3. Heart rate during continuous cycle
exercise in a 37-year-old man with partial myophosphorylase deficiency under
conditions that corresponded to fasting, spontaneous second wind, and glucose
conditions in patients with complete myophosphorylase deficiency. Note the
absence of a change in work capacity with prolonged exercise and glucose,
in contrast to the results for a typical patient with McArdle disease in Figure
1.
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OXYGEN UTILIZATION AND DELIVERY IN EXERCISE
Increased work capacity with the spontaneous second wind and the glucose-induced
second wind was attributable to progressive increases in peak rates of muscle
oxidative phosphorylation. Initial peak O2 in typical patients
with McArdle disease was 1.02 ± 0.33 L/min (13.0 ± 2.0 mL ·
kg-1· min-1). With the spontaneous
second wind, oxidative capacity increased more than 25%, with peak O2 rising to 1.28 ± 0.39 L/min (16.5 ± 3.1 mL ·
kg-1· min-1; P<.001), and with the glucose-induced second wind, O2 rose more than 20% further to 1.55 ± 0.50 L/min (19.9 ±
3.9 mL · kg-1· min-1; P<.001) (Figure 4).
Peak cardiac output was similar during each exercise condition (Figure 4). In contrast, peak systemic AV oxygen difference rose
progressively, from 6.8 ± 1.0 mL/dL at 7 ± 1 minutes of exercise,
to 8.6 ± 1.7 mL/dL (P<.001) after a spontaneous
second wind, and to 9.8 ± 1.5 mL/dL (P<.001)
after a glucose-induced second second wind (Figure 4) consistent with enhanced oxidative phosphorylation attributable
to improved substrate availability.
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Figure 4. Oxygen uptake (O2)
(A) and the physiological components of oxygen uptake, cardiac output (B)
and systemic arteriovenous (AV) oxygen difference (C) corresponding to the
time and conditions of exercise as indicated in Figure 2. Symbols are the
same as in Figure 2. Note the far higher oxidative capacity and peak AV oxygen
difference in the first 6 to 8 minutes of exercise in the patient with residual
enzyme activity. In contrast, peak cardiac output is similar in all subjects.
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In the patient with residual myophosphorylase, peak O2
in the first 6 to 8 minutes of exercise was 2.22 L/min (22.3 mL · kg-1· min-1), almost 2 times the mean level
of patients with complete myophosphorylase deficiency (Figure 4). The difference in initial oxidative capacity between
this patient and those with complete myophosphorylase deficiency is evident
in comparing the relationship between oxygen uptake and cardiac output (Figure 5). In patients with complete myophosphorylase
deficiency, there is a significant linear relationship (R2 = 0.82) between oxygen uptake and cardiac output. However,
the level of increase in oxygen utilization relative to oxygen delivery by
the circulation is low compared with that of the patient with residual myophosphorylase
activity whose O2- relationship is similar to that
of healthy subjects (Figure 5).
This difference is attributable to an almost 2-fold higher level of muscle
extraction of available oxygen (peak systemic AV oxygen difference, 12.0 mL/dL)
compared with patients with complete enzyme deficiency (peak AV oxygen difference,
6.8 ± 1.0 mL/dL) and is consistent with enhanced availability of substrate
for oxidative phosphorylation attributable to residual glycogenolysis.
In contrast to all individuals with complete enzyme deficiency, neither
sustained exercise nor glucose infusion substantially affected peak O2 or AV oxygen difference in this patient (Figure 4).
HEART RATE, VENTILATION, AND CARDIAC OUTPUT RESPONSES TO EXERCISE
In patients with complete myophosphorylase deficiency, heart rate at
the workload that was maximal in the first 6 to 8 minutes of exercise was
36 ± 8 beats/min lower after the spontaneous second wind, and heart
rate at the workload that was maximal after the spontaneous second wind was
25 ± 5 beats/min lower after the glucose-induced second wind. Correspondingly,
the ventilatory equivalent for oxygen fell from 49 ± 14 to 34 ±
12 (P<.001) after the spontaneous second wind
but did not change after the glucose-induced second wind. In the first minutes
of exercise, was high relative to oxygen uptake (/O2, 12.2 ± 1.9), indicating that the level of oxygen delivery
by the circulation in relation to oxygen uptake by working muscle was more
than twice the normal value of approximately 5 (ie, 5 L of increase in cardiac
output per 1 L of increase in O2).15
The /O2 fell to 9.1 ± 1.5 (P<.001) after the spontaneous second wind and to 7.9
± 1.0 (P = .03) during peak exercise after
the glucose-induced second wind (Figure 6).
In contrast to each patient with complete myophosphorylase deficiency,
prolonged exercise and glucose did not substantially influence the relationship
between heart rate, ventilation, and workload in the patient with residual
enzyme activity (Figure 3 and Table 1). The initial /O2 in this patient was virtually normal (6.2) and did not change with
prolonged exercise or glucose (Figure 6).
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Fuel Availability and Metabolism at Rest and During Peak Exercise*
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FUEL AVAILABILITY AND UTILIZATION
In patients with complete myophosphorylase deficiency, free fatty acid
levels were lowest during peak exercise at 7 ± 1 minutes of exercise
and were similar during peak exercise after a spontaneous second wind and
after glucose infusion. Lactate levels fell from rest and were lowest at 7
± 1 minutes of exercise (P<.05). The spontaneous
second wind was associated with a small but consistent increase in lactate
levels from 5.1 ± 1.4 mg/dL (0.57 ± 0.16 mmol/L) to 6.1 ±
1.2 mg/dL (0.67 ± 0.13 mmol/L) (P = .003),
implying increased availability of blood glucose–derived pyruvate. The
glucose-induced second wind was associated with a further increase in lactate
level to 10.9 ± 2.6 mg/dL (1.21 ± 0.29 mmol/L) (P<.001), consistent with a further increase in glucose-derived pyruvate.
Fuel mix as indicated by the respiratory exchange ratio was similar during
peak exercise under each condition (Table
1). After the spontaneous second wind, exercise at the workload
that was maximal at 7 to 8 minutes of exercise resulted in a fall in the respiratory
exchange ratio from 0.98 ± 0.09 to 0.80 ± 0.05.
In the patient with residual myophosphorylase activity, high oxidative
capacity in the first 6 to 8 minutes of exercise was associated with an increase
in blood lactate levels, in contrast to every patient with complete phosphorylase
deficiency (Figure 7). Increased
carbohydrate oxidation in this patient was indicated by the fact that the
respiratory exchange ratio was substantially higher than in patients with
complete myophosphorylase deficiency (Table
1). Blood levels of glucose and free fatty acids at rest and during
exercise were similar to those of other patients with McArdle disease (Table 1).
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Figure 7. Venous lactate levels at rest
and during peak exercise at the times and conditions indicated in Figure 2.
Symbols are the same as in Figure 2.
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COMMENT
The major findings of our study are as follows: (1) The spontaneous
second wind phenomenon in McArdle disease is attributable to a limitation
in muscle oxidative phosphorylation that is most severe in the first 6 to
8 minutes of exercise and to a substantial increase in muscle oxidative capacity
that occurs as exercise is prolonged. (2) A glucose-induced second second
wind exists that is due to a further increase in the peak rate of muscle oxidative
phosphorylation. (3) The oxidative deficit that accompanies complete myophosphorylase
deficiency is largely normalized in a patient with a small amount of residual
enzyme activity. (4) This normalization of oxidative capacity in the first
minutes of exercise virtually abolishes the spontaneous second wind and glucose-induced
second wind responses.
Since its initial description by Pearson and colleagues,4
the spontaneous second wind has been recognized to be a typical clinical feature
of McArdle disease11 that is characterized
by low exercise capacity in the first minutes of sustained exercise followed
by an abrupt improvement in exercise tolerance so that exercise that produced
fatigue and tachycardia only moments before can be sustained virtually indefinitely.6-7 This phenomenon has generally been
interpreted to be a consequence of impaired anaerobic glycogenolysis and to
represent a transition from impaired anaerobic to normal oxidative metabolism.4-7 However,
our results indicate that the spontaneous second wind relates specifically
to the fact that blocked glycogenolysis eliminates a fuel that is critical
for normal oxidative metabolism and makes muscle oxidative capacity dependent
on and fluctuate with changing availability of extramuscular fuels. In patients
with typical McArdle disease with a complete absence of muscle phosphorylase,
a nadir of fuel availability and oxidative capacity occurs in the first 6
to 8 minutes of sustained exercise. Our patients developed fatigue and tachycardia
at low levels of exercise because of a peak oxygen utilization of only 13.0
± 2.0 mL · kg-1· min-1—a
level that is similar to that in patients with mitochondrial myopathies.16-17 This illustrates the critical role
of glycogen as an oxidative fuel in the transition from rest to exercise.
Healthy subjects achieve maximal rates of oxygen utilization within 3 to 5
minutes of sustained exercise by increasing systemic AV oxygen difference
(ie, the extraction of available oxygen from blood) 3-fold from resting levels
of 4 to 5 mL/dL to about 15 mL/dL in concert with maximally increasing systemic
oxygen transport (cardiac output).18-19
In our patients, although peak cardiac output was achieved by 7 ± 1
minutes of exercise, peak AV oxygen difference was only 6.8 mL/dL, ie, approximately
half that of healthy subjects, consistent with a severely restricted capacity
of muscle to extract available oxygen from blood because of substrate-limited
oxidative phosphorylation.
Between minutes 8 and 15 of sustained cycle exercise, each patient with
complete myophosphorylase deficiency developed a spontaneous second wind with
an increase in exercise capacity and a fall in exercise heart rate.4-5,7 A level of exercise
that initially produced fatigue and a heart rate of 166 ± 6 beats/min
became easily tolerated and produced a heart rate of 130 ± 12 beats/min
after the second wind. Increased work capacity and the fall in heart rate
were due to an approximately 25% increase in peak oxygen utilization. Exercise
heart rate is directly proportional to relative exercise intensity expressed
as a percentage of maximal oxidative capacity.19
Thus, heart rate is maximal at maximal oxidative capacity, 75% of maximal
at 75% of maximal oxidative capacity, and so on. Accordingly, an increase
in muscle oxidative capacity results in a proportional fall in exercise heart
rate. The 36-beat/min drop in heart rate in our patients after the onset of
the spontaneous second wind corresponds closely to that predicted from the
measured increase in oxidative capacity. Improved oxidative capacity with
a fall in exercise heart rate at a given absolute exercise workload occurs
in healthy subjects after prolonged exercise conditioning. However, the predominant
physiological mechanism is a higher cardiac stroke volume and a higher peak
level of cardiac output.18 In the second wind
phenomenon, peak cardiac output is unchanged, whereas muscle capacity for
extracting available oxygen increases, consistent with an increased level
of fuel availability and oxidation.
Although the onset of a spontaneous second wind has been interpreted
to signify a transition to normal muscle metabolism and normal exercise capacity,7 our results demonstrate that exercise and oxidative
capacity remain limited by fuel availability. This is evident in the fact
that glucose administration resulted in an additional second wind attributable
to a more than 20% increase in peak oxygen uptake above the level achieved
after a spontaneous second wind. Exercise that caused fatigue and tachycardia
after a spontaneous second wind was more easily tolerated at a heart rate
25 ± 6 beats/min lower after glucose.
Our results indicate that the fundamental oxidative limitation in complete
myophosphorylase deficiency is absence of glycogen-derived pyruvate to support
oxidative phosphorylation and that the spontaneous and glucose-induced second
winds represent improved oxidative capacity that results from increased availability
of extramuscular fuels. The fuel crisis is maximal in the transition from
rest to exercise because of the combination of absent glycogenolysis and low
availability of free fatty acids and of glucose-derived pyruvate,20 as indicated by low blood levels of free fatty acids
and of lactate in the first minutes of exercise (Table 1 and Figure 7). Increased oxidative capacity in a spontaneous second wind has been correlated
with increased availability and oxidation of free fatty acids,5-6
and our results confirm higher free fatty acid levels with the onset of a
second wind (Table 1). However,
we believe that enhanced utilization of blood glucose may also be critical.
This conclusion is supported by previous observations by our group that glucose
uptake during exercise is substantially higher in patients with McArdle disease
than in control subjects.21 In addition, this
study provides the novel observation that blood lactate level increases with
the onset of the second wind (Figure 6),
implying that increased availability of glucose-derived pyruvate is an important
contributor to the spontaneous second wind. The further increase in muscle
oxidative capacity after glucose administration correlates with increased
cellular availability of glucose-derived pyruvate as indicated by a further
increase in blood lactate levels (Figure 7). The fact that the respiratory exchange ratio remains low after
glucose administration suggests that the metabolic benefit may involve pyruvate-mediated
expansion of the tricarboxylic acid cycle via anaplerosis with resultant enhanced
oxidation of noncarbohydrate fuels.22
Despite the increased oxidative rate achieved with a glucose-induced
second wind, peak O2 and systemic AV oxygen difference remained
low compared with those of healthy subjects, indicating that blood-borne fuels
cannot fully substitute for glycogen in oxidative metabolism. This accords
with the observation that complete glycogen depletion in healthy humans causes
fatigue and a dramatic 40% to 50% decrease in maximal aerobic capacity.20, 23-24 The unique role of
glycogen in muscle oxidative metabolism is underscored by our findings in
an unusual patient with a small amount of residual myophosphorylase activity.
Peak work and oxygen uptake and the level of oxygen utilization relative
to oxygen delivery by the circulation within the first 6 to 8 minutes of exercise
in this patient were far higher than in patients with McArdle disease with
complete myophosphorylase deficiency (Figure
4 and Figure 5). This
difference in oxidative capacity from patients with complete myophosphorylase
deficiency was accounted for by the fact that systemic AV oxygen difference
(12.0 mL/dL) was almost double that of other patients with McArdle disease
during the first minutes of exercise (6.8 ± 1.0 mL/dL) and was approximately
25% greater than the mean of typical patients with McArdle disease under conditions
of a glucose-induced second wind (9.8 ± 1.5 mL/dL), consistent with
enhanced availability of substrate for oxidative phosphorylation. We suggest
that this enhanced substrate availability is a consequence of the small level
of preserved glycogenolysis in this patient. Consistent with this interpretation
is the finding of an increase in blood lactate levels in the first 7 to 8
minutes of exercise in this patient in contrast to all patients with complete
myophosphorylase deficiency (Figure 7).
Furthermore, increased oxidative capacity was associated with an increased
level of carbohydrate oxidation as indicated by a higher respiratory exchange
ratio in this patient compared with those with complete myophosphorylase deficiency
(Table 1), indicating increased
availability of carbohydrate for oxidation. Blood glucose and free fatty acid
levels were similar to those of patients with typical McArdle disease, and
differences in the turnover and transport of these fuels are unlikely to account
for this difference in substrate availability. That so small a residual capacity
for glycogenolysis is able to meet oxidative fuel requirements may seem surprising
but is consistent with the observation that muscle oxidative capacity in healthy
humans is maintained until glycogen depletion is complete.23, 25
The fact that residual glycogenolysis in McArdle disease at once enhanced
oxidative rate and virtually abolished the second wind phenomenon confirms
the conclusion that the spontaneous second wind and the glucose-induced second
wind are the direct result of glycogen-limited oxidative metabolism.
These results provide a framework for differentiating symptoms related
to impaired aerobic from deficient anaerobic glycogenolysis in McArdle disease.
They indicate that fatigue and tachycardia with moderate exercise and fluctuations
in exercise capacity and in cardiopulmonary responses that are characteristic
of the second wind phenomenon are consequences of substrate-limited oxidative
phosphorylation. They confirm that glycogen-derived pyruvate is required both
to fuel maximal rates of muscle oxidative phosphorylation and to buffer oxidative
metabolism during fluctuations in the availability of extramuscular fuels,
especially in the transition from rest to exercise.26
They also suggest that premature muscle fatigue, cramping, and rhabdomyolysis
with intense exercise are attributable to limited substrate-level phosphorylation
when glycogenolysis is either blocked or severely limited. Furthermore, since
anaerobic energy demands increase when oxidative capacity is low, the combined
deficit in aerobic and anaerobic glycogenolysis results in a vicious cycle
of impaired energy availability to account for the spectrum of exercise intolerance
in McArdle disease.
AUTHOR INFORMATION
Accepted for publication May 14, 2002.
Author contributions: Study
concepted and design (Drs Haller and Vissing); acquisition
of data (Drs Haller and Vissing); analysis and interpretation
of data (Dr Haller); drafting of the manuscript
(Dr Haller); critical revision of the manuscript for important
intellectual content (Dr Vissing); statistical expertise (Dr Haller); obtained funding (Dr Haller); administrative, technical, or material support (Dr Haller); and study supervision (Dr Haller).
This study was supported by a grant from the Muscular Dystrophy Association,
Tucson, Ariz (Dr Haller), and by a Veterans Affairs Merit Review, Department
of Veterans Affairs, Washington, DC (Dr Haller).
We thank Salvatore DiMauro, MD, for providing mutation analysis and
patient referrals. We are grateful for the expert assistance of Karen Chafee,
RN, Amy Abbott, RN, Phil Wyrick, MS, Gail Reiman, and Karen Ayyad for the
performance of these studies.
Corresponding author and reprints: Ronald G. Haller, MD, Neuromuscular
Center, IEEM, 7232 Greenville Ave, Suite 435, Dallas, TX 75231.
From the Neuromuscular Center, Institute for Exercise and Environmental
Medicine of Presbyterian Hospital, The Veterans Affairs Medical Center, and
The University of Texas Southwestern Medical Center, Dallas (Dr Haller); and
the Copenhagen Muscle Research Center and Department of Neurology, Rigshospitalet,
University of Copenhagen, Copenhagen, Denmark (Dr Vissing).
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