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An oxidative defect in metabolic myopathies Diagnosis by noninvasive tissue oximetry.

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An Omdative Defect in Metabolic
Myopathes: Diagnosis by Noninvasive
Tissue Ownetry
William Bank, MD,” and Britton Chance, PhDi
Metabolic myopathies due to a variety of enzymatic deficiencies are well recognized. The dynamics of oxygen delivery
and utilization during exercise have not been observed previously in these disorders. We used a noninvasive optical
technique to measure oxygen consumption in the exercising limb in normal subjects and patients with metabolic
myopathies. We measured near-infrared spectra of hemoglobin in the gastrocnemius muscle during treadmill exercise
in 10 normal subjects, 1 patient with cytochrome c oxidase deficiency, 2 patients with myophosphorylase deficiency,
3 patients with phosphofructokinase deficiency, and 2 patients with carnitine palmityl transferase deficiency. All
normal subjects demonstrated a sustained deoxygenation during exercise, indicating an efficient utilization of delivered
oxygen. The patient with cytochrome c oxidase deficiency demonstrated consistent oxygenation during exercise,
indicating an underutilization of delivered oxygen. In the patients with myophosphorylase or phosphofructokinase
deficiency, abnormal oxgenation during exercise indicated an oxidative defect due to a lack of pyruvate production.
In the patients with myophosphorylase deficiency, changes in oxidation coincident with glucose utilization and “the
second wind phenomenon” were observed. Patients with carnitine palmityl transferase deficiency demonstrated a
normal deoxygenation during exercise. Noninvasive tissue oximetry during exercise demonstrates specific abnormalities in a variety of metabolic myopathies, indicating abnormal oxygen utilization, and will be a useful addition to the
clinical investigation of exercise intolerance.
Bank W, Chance B. An oxidative defect in metabolic myopathies: diagnosis by
noninvasive tissue oxirnetry. Ann Neurol 1994;36:830-837
Metabolic myopathies due to a variety of inborn errors
result in exercise intolerance, weakness, and acute
muscle injury. These symptoms are the result of enzymatic defects that impair the utilization of fuels required for energy production during exercise. Such
“bioenergetic” defects are well recognized in glycogen
metabolism (myophosphorylase and phosphofructokinase [PFK}), lipid metabolism (carnitine palmityl
transferase [CPT}), and respiratory chain defects in
mitochondria [l-41. Exercise intolerance is typically
manifested in these conditions as muscle injury and
weakness. Although not well understood, the dynamics
of such injury is ultimately thought to be due to a
deficiency in adenosine triphosphate (ATP) IS]. The
adequate delivery of oxygen as well as substrates (glucose and free fatty acids [FFAs)) necessary for ATP
formation may be stimulated by the accumulation of inorganic phosphate (Pi), adenosine diphosphate (ADP),
and its breakdown products during muscle exercise 161.
To date, investigations of these metabolic disorders
have relied on the biochemical analysis of muscle bi-
opsy specimens. Noninvasive investigations, such as
magnetic resonance spectroscopy (MRS), give good evidence of bioenergetic differences but do not address
differences in oxygen consumption in these disorders.
We therefore investigated the dynamics of oxygen
delivery and utilization before and during exercise in
patients with metabolic myopathies. McCully and
coworkers [ 7 ) demonstrated a strong correlation between in vivo phosphocreatine kinetics measured by
MRS and oxygen resaturation measurements following
exercise in normal adults.
We used a noninvasive optical technique that permits in vivo measurements of tissue oxygenation and
deoxygenation as reflected in the near-infrared spectrum of hemoglobin to demonstrate the dynamic process of oxygen delivery and consumption in an exercising limb. In addition, we concurrently measured
changes in blood volume within the muscle concomitant with exercise to ensure an appropriate hemodynamic response. This technique accurately reflects
prompt changes in tissue deoxygenation and changes
in muscle microvasculature, thereby demonstrating the
From the Departments of *Neurology and ?Biophysics and Biochemistry, University of Pennsylvania, Philadelphia, PA.
Address correspondence to D r Bank, Department of Neurology,
Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia’ PA 17104’
Received Apr 27, 1994, and in revised form Jul 12. Accepted for
publication Jul 14, 1994.
830 Copyright 0 1994 by the American Neurological Association
adaptation of oxygen delivery and utilization in normal
subjects during exercise as well as during postexercise
We examined patients with myophosphorylase,
PFK, CPT, or cytochrome c oxidase deficiency to investigate whether an imbalance in oxygen delivery and
utilization occurs in these bioenergetic disorders. Such
an imbalance is signaled by a n increase in hemoglobin
saturation during exercise, instead of decreased hemoglobin saturation observed in normal individuals.
T h e s e observations lend further insights into t h e diverse adaptive capacity of human muscle metabolism
as well as the specific abnormalities seen in these wellrecognized metabolic abnormalities. Observing the balance of delivery and utilization of oxygen during exercise offers a promising new clinical technique for t h e
investigation of muscle fatigue and exercise intol-
Materials and Methods
All patients with metabolic myopathies had muscle biopsyproved diagnoses. None demonstrated muscle weakness and
all were able to perform the exercise protocol described. The
patients included 1 with cytochrome oxidase deficiency, 3
with myophosphorylase deficiencies, 3 with PFK deficiencies,
and 2 with CPT deficiencies. Patient histories are reviewed
Clinical History
A 42-year-old man
(Patient 1) had lifelong exercise intolerance manifested as
fatigue associated with premature exertional dyspnea and
tachycardia. The symptoms were evident since childhood but
most striking in adolescence when he attempted to exercise
vigorously. Exercise tolerance may have worsened somewhat
as an adult. He had no history of muscle cramping, although
he experienced burning in the legs during trivial exercise.
There was no history of pigmenturia or renal failure. The
patient noted a chronic difficulty maintaining his weight and
consumes as much as 6,000 calories a day to do so. There
was no history of cardiac or pulmonary disease and the patient took no medications. H e had no family history of similar
At presentation the patient was a normally developed,
thinly muscled man. Cardiopulmonary findings were normal.
Cranial nerves were normal as was muscle strength except
for mild weakness in the legs. Laboratory tests showing normal results included hematocrit, hemoglobin, thyroid function studies, urinalysis, and serum electrolyte, calcium, magnesium, and glucose measurements. Creatine kinase (CK)
activity was normal. A muscle biopsy specimen showed a
deficiency in cytochrome c oxidase.
shortness of breath during exercise and could generally prevent muscle injury by heeding the early symptoms of muscle
contracture. She had normal muscle bulk and strength, and
findings on cardiopulmonary examination were normal.
Study of a muscle biopsy specimen confirmed myophosphorylase deficiency.
A 36-year-old woman (Patient 3) experienced repeated
exercise intolerance with muscle contracture but rare myoglobinuria. She described a typical “second wind” phenomenon and had biopsy-proved myophosphorylase deficiency.
A 37-year-old man (Patient 4) had recurring exercise intolerance and episodes of myoglobinuria. He had normal
strength and biopsy-proved myophosphorylase deficiency.
(Patient 5 ) experienced recurring episodes of muscle stiffness
associated with exercise. He had chronically elevated CK
but no history of pigmenturia or renal failure. The exercise
intolerance was limited to muscle spasms, particularly in the
back and buttocks, and was not associated with shortness
of breath or tachycardia. ”P MRS during rest and exercise
suggested the diagnosis of PFK deficiency, which was confirmed by muscle biopsy.
A 44-year-old man (Patient 6) had lifelong exercise intolerance with rare episodes of myoglobinuria. The diagnosis of
PFK deficiency was confirmed by 31PMRS as well as muscle
A 60-year-old man (Patient 7) was relatively sedentary and
rarely experienced exercise intolerance. He demonstrated an
elevated serum C K and uric acid levels and absence of muscle
PFK in biopsy specimens.
A 33-year-old woman
(Patient 2) experienced exercise intolerance associated with
contracture and pigmenturia. She had no history of weakness
or muscle atrophy and subsequent examination of a muscle
biopsy specimen confirmed myophosphorylase deficiency.
This patient did not experience significant tachycardia or
A 50year-old man (Patient 8 ) had a 20-year history of recurrent
myoglobinuria without exercise intolerance. The patient had
normal muscle bulk and strength, and cardiopulmonary findings were normal. CPT was absent in muscle.
A 32-year-old man (Patient 9 ) experienced recurring muscle pain and myoglobinuria during episodes of fasting during
exercise. Several episodes occurred during anorexia associated with febrile illness. CPT was absent in muscle.
Evaluation of Tissue Oxygenation and Changes in
Tissue Blood Volume
To test the rationale of this study, a noninvasive optical
method was used to study muscle deoxygenation during exercise by measuring a differential response to a pair of wavelengths (850 and 760 nm on each side of the equal absorbance point near 800 nm) in the near-infrared spectrum
of hemoglobin. Concurrently, blood volume changes could
be measured as the sum of the responses of the two wavelengths. The contributions of the signals at 760 and 850 nm
are adjusted to avoid “crosstalk” of deoxygenation and measurements of blood volume. The dual-wavelength spectrophotometer consists of an optic probe having two flashlight
bulbs operated at low voltage appropriate for red light emission. Two interference filters select the appropriate wavelengths, 760 to 850 nm, and have a half-bandwidth of 10 to
50 nm, appropriate to the broad bands of hemoglobin within
the infrared spectrum. Silicon detectors sensitive to this region of the infrared spectrum are used. The lights illuminate
Bank and Chance: Oxidative Defect in Metabolic Myopathies
the tissue sample intermittently so that the dark level may
be measured and corrected. The circuit is stable and capable
of responding to an absorbancy change of lo-’. The signal
from muscle is larger, with a 20% change in deoxygenation
corresponding to a change of 0.08 in absorbancy {8, 91.
1 1
OPTICAL FIELD. The pattern of photon migration is “banana
shaped,” originating at the iight sources and terminating at
the detectors. To provide adequate penetration of light to
the gastrocnemius muscle, a spacing of 4 cm between input
and output light was selected. This is based on principles of
photon migration and pinhole scans of photon migration in
model systems of similar geometry { 10, 111. The two fields
penetrate to a mean depth of 2 cm. An approximate calibration of this instrument is obtained by measuring complete
deoxygenation of hemoglobin and myoglobin in an ischemic
limb using a tourniquet cuff. Measurements of relative saturation of hemoglobin are obtained during reactive hyperemia
following the recovery from exercise. The contribution of
myoglobin to these observations is estimated to be about
30% as determined in animal muscle studies.
All patients and control subjects exercised on a low-speed treadmill (2 mph at 0-degree inclination). All patients with exercise intolerance achieved maximal
effort with this protocol and successfully completed exercises
during oximetry studies. The probe is placed over the longitudinal plane of the gastrocnemius muscle, with the axis of
lights and detectors parallel to the limb. Care is taken to
avoid the saphenous vein. Condensation of moisture on the
detectors is eliminated by interposing a thin sheet of transparent plastic (Saran Wrap) between the skin and the detectors.
The detector is held rigidly in place by Velcro straps and no
motion artifact is observed. Baseline data are calibrated at a
differential response between the wavelengths at 850 and
760 nm: A shift to the former indicates tissue oxygenation
and a shift to the latter indicates tissue deoxygenation. Subjects are permitted to stand briefly before exercising, to adjust baseline blood flow.
Changes in absorption are continuously monitored during
rest, exercise, and recovery. Treadmill exercise is performed
for 5 to 10 minutes followed by sedentary rest. Treadmill
speed was occasionally increased to 4 mph to test exercise
tolerance. An intravenous infusion of 25 gm of dextrose was
given over 1 hour in several subjects. An oral load consisted
of 7 5 gm of glucose.
Absorbance Decrease
= Blood Volume
Absorbance Increase
-0 06-
= Deoxygenation
I rnin
Fig 1 . A typical normal subject, treadmill exercise at 2 mph.
Noinzal subjects (n = 10). iAi A decreased absorbance 1760 +
850 nmi indicates a decrease in blood volume during exercise.
(B) Prompt deoxygenation (increased absorbance, 760 - 850
nmi occurred with the initiation of exercise and was maintained as a steady state. Values returned to baseline during postexercise recozieevy.
Normal Subjects
Ten healthy age- and sex-matched normal control subjects were tested. Subjects were not fasting and relatively sedentary, and they walked leisurely on the treadmill at 2 mph. The blood volume tracing (absorbance
760 + 850 nm) demonstrated a decrease of blood
volume normally seen in exercising muscle (Fig 1A).
The increase in absorbance at 760 nm with respect to
absorbance at 850 nm reflects deoxygenation of hemoglobin and occurred promptly at the start of exercise
in all normal control subjects (Fig 1B). All normal individuals demonstrated a period of deoxygenation during
exercise. Of the metabolic myopathies examined, only
832 Annals of Neurology Vol 36 No 6 December 1994
CPT deficiency was associated with this normal response (Fig 2). Tissue deoxygenation of hemoglobin
reached a steady state within 30 seconds and was maintained throughout the remainder of exercise. When
exercise ceased, a prompt return to baseline and a concurrent hyperemia were noted in the resting muscle of
all normal control subjects. One subject underwent a
24-hour fast as well as an oral glucose load with no
effect on the above data.
Patients with Metabolic Myopathies
All subjects were able to perform the exercise protocol
without fatigue or weakness. A normal decrease in
blood volume occurred in all subjects during exercise
and a normal reactive hyperemia was noted during rest
after exercise.
this disorder demonstrated a prompt and sustained
oxygenation during exercise while blood volume responses were normal (Figs 3A, 3B). Exercise was
maintained (at 2 mph) for 5 minutes without weakness.
An early and excessive tachypnea and tachycardia were
noted. Similar results were observed at 3 and 4 mph.
A prompt and pronounced deoxygenation occurred at
the end of exercise. Complete deoxygenation was measured by applying a tourniquet to the thigh shortly
before stopping exercise. Postexercise deoxygenation
fell to within 295 of complete anoxia in this patient
(Fig 4A).
1 = 1 Blood Volume
(760+850 n m )
Absorbance Decrease
0 121
O .04
0 = Normal
v m
= McArdle’s
= Cyt. o x
Absorbance Decrease
0. I
1 = Oxygenation
( 760 - 850 n m )
Speed ( m p h )
Fig 2. Oximety during treadmill exercise. All normal subjects
In = 10) demonstrated sustained deoxygenation during exercise.
Oxygenation during exercise was noted in glycolytic and mitochondrial disorders but not in carnitine palmityl transferase
(CPT) deficiency. PFK = phosphofructokinase deficiency; Cyt.
Ox. = qtochrome c oxidase.
-0 I
change was associated with painful fatigue in the exercised muscle. Several patients described a typical subjective “second wind” during repeated exercise. During such intervals, oximetry shifted from oxygenation
to deoxygenation and was sustained for 7 to 10 minutes (Figs 6A, 6B). A prolonged oxygenation was
noted during subsequent rest (Fig 6C).
After 50 gm of intravenous glucose was administered, Patient 3 demonstrated a 70% decrease in the
rate of oxygenation and was able to sustain 20 minutes
of symptom-free exercise (Fig 7A). Oxygenation during exercise decreased 68% in Patient 4 after an oral
glucose load (Fig 7B).
- 0 10
0 121
Absorbance Decrease
2 min
Fig 4. (A) Sustained oxygenation during exercise in the same
patient represented in Figure 3. Complete deoxygrnation was induced by a tourniquet to the thigh at rest. Postexercise deoxygenation fell to 2% of complete anoxia. (B) Blood volume responses
during exercise are normal.
Absorbance Decrease = Blood Volume
(760 + 850 n m )
-0. I 0
Fig 3. (A)Cytochrome c oxidase-deficient patient, treadmill exercise at 2 mph, gastrocnemius muscle. A prompt and sustained
oxygenation occurs during exercise in this mitochondrial disorder. (Bi Blood volume responses during exercise are normal.
All 3 patients with
McArdle’s disease demonstrated an abnormal muscle
oxygenation during exercise while blood volume
changes were consistently normal. When initiating exercise after prolonged rest, patients often showed a
prompt and sustained oxygenation that returned to deoxygenation with rest (Fig 5). On other occasions, a
prompt but brief (30-second) deoxygenation was followed by a sudden switch to oxygenation that gradually
progressed throughout sustained exercise. This sudden
PHOSPHOFKUCTOKINASE DEFICIENCY. All 3 PFK-deficient subjects demonstrated a paradoxical and sustained
oxygenation during exercise (Fig 8A). A transient (30second) deoxygenation was occasionally observed, followed by a sudden and sustained oxygenation for the
remainder of exercise. As in McArdle’s disease, this
shift was associated with symptoms of fatigue. No subjective “second wind” was elicited and there was no
response to an intravenous glucose infusion. Prompt
and sustained oxygenation during exercise was also
seen (Fig 8B).
patients with CPT deficiency showed a normal deoxygenation in response to exercise. Both subjects had
Bank and Chance: Oxidative Defect in Metabolic Myopathies 833
Absorbance Decrease
1 = Oxygenation
Pre Glucose
(760- 850 nm 1
Absorbonce Decrease
= Oxy~enol~on
1760- 8 5 0 n m i
a -0.08
Absorbance Decrease = Oxygenation
1 min
P r e Glucose
Fig 5. Patient with McArdle's disease, treadmill exercise at 2
mph, gastrocnemius muscle. A prompt sustained oxygenation occurred during exercise after a prolonged rest. (Blood volume measurements were normal but omitted from this figure.)
Post Glucose
0 04
-0 02
Absorbonce lncreose = Deoxygenotion
( 7 6 0 - 8 5 0 nml
1 min
Fin 6. "Second wind" in a patient with McArdlei- disease.
ial A brief period of deoxygenation was jbllowed (b) by oxygenation during sustained exercise. demonstrating the rapid
depletion of a metabolic substrate. A subsequent Jb$t to deoxygenation was coincident with improved exercise capacity.
( C I Postexercise recovery was prolonged.
Fig 7. Decreased oxygenation in a patient with McArdle's disease afier glucose load. (A)The rate of oxygenation decreased by
70% after 50 gm of intravenous glucose was administered.
(B, A similar observation was made after an oral glucose load.
increased deoxygenation with increased work (Fig 9)
and values returned to normal with rest. A 36-hour
fast in 1 subject (Patient 8) caused no subjective symptoms and did not significantly alter his oximetry measurements during exercise.
The major observation of this investigation is the impaired utilization of oxygen in patients with various
metabolic myopathies as assessed by a noninvasive optical probe measuring the oxygenation of hemoglobin
and myoglobin. This technique permits repeated accurate observations of tissue oxygenation during rest and
exercise. We are able to measure the balance between
the delivery of oxygen by the vasculature and utilization of oxygen by mitochondria. Continuous light tissue spectrometers are sensitive and accurate trend indi-
Absorbonce Decrease = Oxygenation
( 760-850 nm )
0 04
-0 08
F i g 8. Phosphofructokinase-deficientpatient, treadmzll exercise
at 2 mph. gastrocnemius muscle. (A)Transient deoxygenation
followed by sustained oxygenation during exercise demonstrates
possible substrate depletion. iBI Sustained oxygenation during
exercise was also seen.
834 Annals of Neurology Vol 36 No 6 December 1994
0. l
Absorbance Increase f = Deoxygenation
0.08 -
Fi g 9. Carnitine palmityl transferase (CPT)-deficient patient,
treadmill exercise at 2 mph, gastrocnemius muscle. A nomal sustained deoxygenation during exercise was noted in both patients
with CPT deficiency.
cators with an excellent signal-noise ratio. Since the
depth of optical penetration in tissue cannot be measured, a quantitative analysis of such trends is not possible. Normal subjects show deoxygenation with
exercise, whereas patients with impaired oxidative
phosphorylation show increased oxygenation.
Energy in exercising muscle is predominantly derived from the aerobic electron transport system within
mitochondria and the fuels consumed by skeletal muscle during exercise are FFAs and glucose 1121. The
alternative anaerobic system breaks down glycogen to
lactic acid and pyruvate; the latter is further metabolized via acetyl coenzyme A (CoA) and the tricarboxylic acid (TCA) cycle [13]. Maximal power output as
measured by ATP turnover is in fact 50% greater in
the oxidation of glycogen than the oxidation of FFAs
[14-16]. Mobilization of these fuels requires stimulation of glycolytic and lipolytic metabolic pathways. The
stimulus for altering substrate availability is the product
of muscle energy metabolism and may be due to the
accumulation of ADP as a result of oxidative phosphorylation [6]. The delivery of these substrates
and increased demands for oxygen depend on exerciseinduced stimulation of the cardiopulmonary and microvascular systems 117, 181. Normally, increased oxygen
supplies are rapidly consumed during exercise, resulting in deoxygenation. The utilization of increased
oxygen supplies is, however, impeded in a number of
inborn errors in muscle metabolism which result in
impaired oxidative phosphorylation. The inability to
utilize increased oxygen supplies therefore leads to increased oxygenation of exercising muscle. We observed distinctive patterns of an imbalance between
oxygen delivery and utilization in patients with metabolic disorders of mitochondria, as well as disorders of
glycogen and glucose metabolism.
Our observations in normal individuals reflect the
prompt response of the cardiovascular system in delivering glucose, fatty acids, and oxygen which are rapidly
utilized, resulting in tissue deoxygenation during sustained exercise. The extent of deoxygenation is dependent on the workload and the degree of exercise conditioning of the normal subject [ 7 , 191. With the
cessation of exercise, a prompt “reoxygenation” occurs
until the delivery of blood and nutrients is normalized
to fuel requirements at rest. Similar responses were
noted in the flexor muscles of the forearm and the
quadriceps muscle during exercise. These muscles
were not consistently tested in our patients and will
require development of consistent exercise protocols
if used in clinical investigations. The gastrocnemius
muscle was effectively exercised and easily observed
during treadmill exercise.
It is recognized that blood flow to the limb is increased on initiating exercise and a decrease of pooled
blood in the limb occurs simultaneously because of
muscle contraction. The highly efficient utilization of
oxygen in normal subjects is illustrated in swift and
sustained deoxygenation during exercise. This observation was consistently seen in all normal subjects. In
contrast, conditioned athletes required exercise demands, a pace faster than 4 mph, to demonstrate sustained deoxygenation during exercise. We therefore
used a standard protocol of 2 mph on a level treadmill
for all our patients and normal control subjects.
Cytochrome c Oxidase Dejicienry
A patient deficient in cytochrome c oxidase has a partial
defect in the electron transport chain that limits the
capacity of mitochondria to generate ATP and results
in inordinate fatigue after minimal exercise. Our patient with this deficiency demonstrated a paradoxical
oxygenation during exercise that was sustained during
modest work; deoxygenation occurred when exercise
ceased. The factors initiating an increased demand for
necessary fuels and oxygen were therefore intact. As
a result of cytochrome c oxidase deficiency, oxidative
phosphorylation was inadequate and greater oxidative
demands for energy production were stimulated, resulting in disproportionate tachycardia and dyspnea
during mild exercise. Increased supplies of oxygen
could, however, not be adequately utilized, resulting
in a paradoxical oxygenation during exercise. Increased
demands for fuel and oxygen ceased with the end of
exercise and returned to resting requirements. The
resting level of tissue oxygenation in this individual was
within 2% of complete deoxygenation as measured
Bank and Chance: Oxidative Defect in Metabolic Myopathies
during tourniquet ischemia (see Fig 4A) on several occasions. The very low oxygen demand and delivery
at rest in this patient may reflect a unique adaptive
conservation presumably due to his inability to utilize
oxygen fully. While the control mechanism for minimizing oxygen delivery at rest is unclear, our observations show that it is distinct from the normal (in this
case, excessive) response of substrate delivery during
exercise. The minimal supply of oxygen at rest is presumably adequate for the limited capacity of this patient since he is symptom free when not exercising.
The prompt and sustained oxygenation of exercising
muscle is a clear indication of a disorder of oxygen
consumption and highly indicative of disordered oxidative phosphorylation. Distinctions between various
blocks within the electron transport system have, to
date, not been noted. We have, however, seen such a
characteristic profile in patients with exercise intolerance in whom no specific metabolic abnormality could
be identified 1201. This suggests the possibility of mitochondrial metabolic defects yet to be identified.
Myophosphoylase Deficiency
Anaerobic glycogenolysis normally produces lactic acid
and pyruvate; the latter is further metabolized via acetyl CoA and the TCA cycle and is the most efficient
source of ATP production relative to oxygen consumption. Glycogen is therefore an important substrate for
maximal oxidative phosphorylation { 141. An absence
of myophosphorylase (McArdle’s disease) blocks anaerobic glycogenolysis and the production of pyruvate
and ATP 1211. All 3 patients with McArdle’s disease
felt fatigue and the symptoms of muscle contracture
during the onset of more vigorous exercise (3-4 mph
on a treadmill). These symptoms were also associated
with abnormal and sustained oxygenation during exercise (see Fig 5) and indicate an oxidative defect
in McArdle’s disease. Previous investigations have
suggested such a possibility 11, 141. During exercise,
2 patients with McArdle’s disease demonstrated a
prompt but brief deoxygenation (30 seconds) followed
by a sharp reversal to a sustained period of oxygenation
without a change in work performed or subjective fatigue (see Fig 6A). The third patient demonstrated a
prompt and sustained oxygenation during exercise. All
3 patients therefore demonstrated impaired oxidative
phosphorylation. The shift to oxygenation in 2 patients
illustrates aerobic substrate depletion, possibly due to
the lack of pyruvate production.
Repeated exercise after a period of rest resulted in
a gradual deoxygenation (see Fig 6B). During this
phase of exercise, patients described subjective improvement in exercise tolerance typical of the “second
wind” phenomenon. They could sustain exercise two
to three times longer without fatigue or muscle tightness. This phenomenon is likely due to the availability
of alternative fuels such as glucose and FFAs 1221 and
reflects improved oxidative phosphorylation. On cessation of exercise, McArdle’s disease patients demonstrated a prolonged recovery to resting tissue oxygenation (see Fig 6C). Normally, the resting state is
recovered within 20 seconds, but these patients required 5 minutes. This may reflect the slow “payoff”
of a bioenergetic debt (ATP) due to the absence of
pyruvate production. Alternative fuels such as glucose
and FFAs are apparently insufficient to fully satisfy substrate requirements in this condition.
Patient 3 demonstrated a gradual and sustained oxygenation with the onset of exercise. After an intravenous infusion of glucose, she experienced improved
endurance and the rate of oxygenation decreased by
70% (see Fig 7A). Patient 4 demonstrated a 68% decrease in oxygenation after an oral glucose load (see
Fig 7B). These observations confirm the ability of patients with McArdle’s disease to effectively utilize glucose as an alternative fuel and partially correct the
secondary oxidative deficiency seen in this disorder.
Improved bioenergetic function in response to glucose
infusions has been noted previously in McArdle’s disease 11, 231.
Phosphofrzlctokinase Deficiency
As in McArdle’s disease, the metabolic defect in PFK
deficiency blocks anaerobic glycogenolysis and, in addition, the alternative pathway of glucose utilization is
blocked 121. Three patients with this disorder demonstrated a consistent oxidative defect during exercise but
did not demonstrate clinical or laboratory evidence of
the “second wind” phenomenon. None improved after
oral or intravenous administration of glucose. On several occasions, these subjects also demonstrated a transient deoxygenation that shifted to a sustained oxygenation after 30 seconds during continued exercise (see
Fig 8). As in McArdle’s disease, this demonstrates substrate depletion presumably due to absence of pyruvate
production. Our observations confirm a secondary oxidative defect in PFK deficiency as previously suspected
in other investigations 124, 251.
836 Annals of Neurology Vol 36 No 6 December 1994
Carnitine Palmityl Transfevase Defciency
The absence of CFT in the mitochondria1 membrane
impairs the incorporation and beta-oxidation of longchain fatty acids. Rhabdomyolysis typically develops in
patients with this disorder when fasting during prolonged exercise [3, 261. The availability of glycogen,
glucose, and short- and medium-chain fatty acids normally prevents exercise intolerance and muscle injury.
Our observations of normal deoxygenation during exercise confirm that oxidative metabolism was normal
in the 2 patients examined (see Fig 9) while on a normal diet. A 36-hour fast did not provoke symptoms or
a change in tissue oximetry during exercise in 1 pa-
tient. The degree and duration of exercise may have
been inadequate to stress oxidative metabolism in this
During exercise, increased oxygen delivery is rapidly
utilized in normal subjects, resulting in tissue deoxygenation. In patients with a bioenergetically inefficient
oxidative system, oxygen delivery increases with exercise without a commensurate increase in oxygen utilization, showing a paradoxical oxygenation during exercise. Our investigations demonstrated evidence for
defects in oxidative phosphorylation in a variety of
metabolic myopathies. Such a defect in cytochrome
oxidase deficiency is not surprising and tissue oximetry
will be useful in screening patients for this and other
disorders of mitochondrial metabolism. In the anaerobic disorders of McArdle’s disease and PFK deficiency,
evidence of oxidative insufficiency is likely due to the
lack of pyruvate production. Dynamic changes in the
utilization of oxygen during exercise demonstrated
substrate depletion in these anaerobic disorders and
adaptations of alternative substrate utilization were
seen in McArdle’s disease. More provocative tests
stressing fatty acid utilization in CPT deficiency may
well show oxidative defects as well.
Noninvasive tissue oximetry is a new and useful clinical technique that permits accurate, repetitive observations of changes in muscle microvascular flow and oxygenation during exercise. The prompt delivery and
utilization of oxygen can be observed. The underutilization of oxygen during impaired oxidative phosphorylation was observed in mitochondrial disorders and also
in myophosphorylase and PFK deficiencies. These observations shed new light on the adaptive mechanisms
in metabolic muscle disorders and will be a useful addition to the clinical investigation of fatigue and exercise
This work was supported by NIH grant HL 44125. Oximetry equipment was provided by NIM (3624 Market Street, Philadelphia, PA
We wish to thank Ms P. Kaufman for her assistance in the preparation of this manuscript. The technical assistance of Mr Cheng Duo,
Ms Quing Yean, and Mr Ed Rachofsy is gratefully acknowledged.
DiMauro S, Bresolin N. Phosphorylase deficiency. In: Engel
AG, Banker BQ, eds. Myology. New York: McGraw-Hill,
Rowland LP, DiMauro S, Layzer R. Phosphofructokinase deficiency. In: Engel AG, Banker BQ, eds. Myology. New York:
McGraw-Hill, 1986:1603-1617
DiMauro S, Papadimitriou A. Carnitine palmityl transferase deficiency. In: Engel AG, Banker BQ, eds. Myology. New York:
McGraw-Hill, 1986: 1697-1704
Morgan-Hughes JA. The mitochondrial myopathies. In: Engel
AG, Banker BQ, eds. Myology. New York: McGraw-Hill,
1986:1709-1 734
5. Karlson J, Saltin B. Lactate, ATP, and CP in working muscle
during exhaustive exercise in man. J Appl Physiol 1970;29:598602
6. Bertocci LA, Haller RG. Impaired phosphocreatine hydrolysis
in exercise in myophosphorylase deficiency determined by ”P
NMR. Neurology 1992;42:387
7. McCully KK, Dotti S, Kendrick K. Simultaneous in vivo measurements of oxygen saturation and PCr kinetics following exercise in humans. J Appl Physiol 1994;77:5-10
8. Chance B, Smith DS, Nioka S, et al. Photon migration in muscle
and brain. In: Chance B, ed. Photon migration in tissues. New
York: Plenum, 1989:121-135
9. Haselgrove J, Wang NG, Chance B. Investigation of the nonlinear aspects of imaging through a highly scattering medium.
Med Phys 1992;19:17-23
10. Wilson BC, Sevick E, Patterson MS, Chance B. Timedependent optical spectroscopy and imaging for biomedical applications. Proc IEEE 1992;80:918-930
11. Hebden JC, Kruger RA. Transillumination imaging performance: spatial resolution simulation studies. Med Phys 1990;17:
12. Felig P, Wahren J. Fuel homeostasis in exercise. N Engl J Med
13. Lewis SF, Haller RG. The parhophysiology of McArdle’s disease: clues to regulation in exercise and fatigue. J Appl Physiol
14. Lewis SF, Haller RG. Human disorders of muscle glycogenolysidglycolysis: the consequences of substrate-limited oxidative
metabolism. In: Taylor AW, ed. Biochemistry of exercise VII.
Champaign, IL Human Kinetics, 1990:211-226
15. Haller RG, Lewis SF. Glucose-induced exertional fatigue in
muscle phosphofructokinase deficiency. N Engl J Med 1991;
16. Pernow B, Saltin B. Availability of substrates and capacity for
prolonged heavy exercise in man. J Appl Physiol 1971;31:416422
17. Pernow B, Saltin B. Muscle metabolism in exercise. New York:
Plenum, 1971
18. Keul J, Doll E, Keppler D. Energy metabolism of human muscle. Baltimore: University Park Press, 1972
19. Chance B, Dait MJ, Chang C. Recovery from exercise-induced
desaturation in the quadriceps muscle of elite competitive rowers. Am J Physiol 1992;162:C766-C775
20. Bank WJ, Tino G, Chance B. Microvascular control in a respiration-deficient limb as measured by non-invasive tissue oxymetry.
Neurology 1992;42:146
2 1. McArdle B. Myopathy due to a defect in muscle glycogen breakdown. Clin Sci 1951;10:13-33
22. Pernow BB, Have1 RJ, Jennings DB. The second wind phenomenon in McArdle’s syndrome. Acta Med Scand Suppl 1967;472:
23. Argov 2, Bank WJ, Maris J, Chance B. Muscle energy metabolism in McArdle’s syndrome by in-vivo phosphorus magnetic
resonance spectroscopy. Neurology 1987;37:1720-1724
24. Argov 2, Bank WJ, Maris J, et al. Muscle energy metabolism
in human phosphofructokinase deficiency as recorded by ”P
NMR spectroscopy. Ann Neurol 1987;22:46-5 1
25. Lewis SF, Vora S, Haller RG. Abnormal oxidative metabolism
and O2 transport in muscle phosphofrucrokinase deficiency. J
Appl Physiol 1991;70:391-398
26. Bank WJ, DiMauro S, Bonilla E, et al. A disorder of muscle
lipid metabolism and myoglobinuria-absence of CPT. N Engl
J Med 1975;292:443-449
Bank and Chance: Oxidative Defect in Metabolic Myopathies
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myopathic, oximetry, metabolico, oxidative, tissue, defects, diagnosis, noninvasive
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