Abnormal oxidative metabolism and 0, transport in muscle phosphofructokinase deficiency STEVEN F. Departments Dallas iX%‘5; and Research
LEWIS, SHOBHANA VORAj-, AND RONALD G. HALLER of Physiology and Neurology, University of Texas Southwestern Medical Center, Veterans Aflairs Medical Center, Dallas, Texas 75,216; and Scripps Clinic Foundation, La Jolla, CaLifbrnia 92037
LEWIS, STEVEN F., SHOBHANA VORA, AND RONALD G. HALLER. Abnormal uxidative metabolism and O2 transport in muscle phosphofructokinase deficiency. J. Appl. Physiol. 70(1): 391-398, 1991.-Humans who lack availability of carbohydrate fuels may provide important models for the study of physiological control mechanisms. We compared seven patients who had unavailability of muscle glycogen and blood glucoseas oxidative fuels due to musclephosphofructokinase deficiency (PFKD) with five patients who had a selective defect in long-chain fatty acid oxidation due to carnitine palmitoyltransferase deficiency (CPTD) and with six healthy subjects. Peak cycle exercisework rate, peak 0, uptake (vo2), and arteriovenous O2difference were markedly lower (P < 0.001) for PFKD patients (23 t 6 W, 14 t 2 ml min-’ kg-l, and 7.1+ 0.5 ml/dl, respectively) than for CPTD patients (142 & 33 W, 31 t 4 ml min-’ kg-‘, and 15.0 ? 0.8 ml/dl, respectively) or healthy subjects (171 t 17 W, 36 t I ml min-’ kg;‘, and 16.4t 0.7 ml/d& respectively). Peak cardiac output (Q) was sim.ilar (P > 0.05) in all three groups, but the slopeof increase in Q (l/min) on 00, (l/min) from rest to exercise (At@Avo,) was more than twofold greater (P < 0.001)for PFKD patients (11.2 t 1.2) than for CPTD patients (4.6 & 0.6) and healthy subjects (4.6 t 0.2). Increasing availability of blood-borne oxidative substrates capable of metabolically bypassing the defect at phosphofructokinase (by fasting plus prolonged moderate exercise to increaseplasmafree tatty acids or by iv lactate infusion) increasedpeak work rate, VO,, and arteriovenous O2 difference, lacked consistent effect on peak &, and normalized Ag/Avoz in PFKD patients. The results extend our previous observations in patients with a block in muscle glycogen but not blood glucose oxidation due to phosphorylase deficiency and imply that specificunavailability of muscleglycogen asan oxidizable fuel is primarily responsible for abnormal muscle oxidative metabolism and associatedexercise intolerance and exaggerated AQ/Avo, in musclePFKD. The findings also endorse the concept that factors closely linked with muscleoxidative phosphorylation participate in regulating A&/A%,, likely via activation of metabolically sensitive muscle afferents. l
l
l
l
l
l
glycogen storage disease;carnitine palmitoyltransferase deficiency; oxygen uptake; cardiac output; arteriovenous oxygen difference; exercise performance; fasting; lactate infusion; free fatty acids; energy metabolism
THE IMPORTANCE
as fuels for human
of muscle glycogen and blood glucose exercise performance is well docu-
t S. Vora is deceased. OMI-7567/91
mented, but their physiological significance is incompletely understood. Studies performed in the late 1960s and early 1970s (l&35) showed a direct relationship between initial glycogen content in active muscle and duration of exercise performance at work rates corresponding to 7545% of maximal O2 uptake (VOW,,,). The classic experiments of Christensen and Hansen (5) demonstrated that the point of exhaustion in exercise lasting 3-6 h closely correlated with a subnormal blood glucose and symptoms of hypoglycemia. There is, however, very limited information on the impact of a virtually complete lack of access to carbohydrate fuels on regulatory mechanisms during exercise in humans. Recent findings in patients with absent glycogen breakdown due to myophosphorylase deficiency (type V glycogen storage disease or McArdle’s disease) suggest that human glycolytic disorders may provide unique experimental models in exercise and fatigue (21). In phos-
phofructokinase deficiency (PFKD; type VII glycogen storage disease), muscle glycogen and blood glucose are unavailable to fuel muscle contraction because they enter glycolysis proximal to the glycolytic block. This results in a striking failure of blood lactate to increase during ischemic exertion in patients with PFKD (33,38), spawning the conventional belief that the exercise intolerance of PFKD primarily relates to defective anaerobic energy supply. However, oxidative phosphorylation normally is the dominant mode of ATP resynthesis supporting the dynamic muscle contractions that compose most common physical activities. As an initial step in defining human PFKD as an experimental model, a major goal of the present study was to determine how unavailability of both muscle glycogen and blood glucose affects oxidative metabolism and exercise performance in patients with PFKD. This was accomplished by comparing peak 0, uptake, its components, cardiac output (reflecting 0, delivery) and arteriovenous oxygen difference (reflecting muscle 0, extraction), and peak exercise workload in patients with PFKD, patients with normal access to muscle glycogen and blood glucose as oxidative fuels but a selective defect in long-chain fatty acid oxidation due to muscle carnitine palmitoyltransferase deficiency (CPTD), and healthy control subjects. In addition, in PFKD patients, interventions designed to increase availability of oxidative substrates capable of metabolically bypassing the defect at phosphofructokinase were used to determine
$1.50 Copyright 0 1991the American
Physiological
Society
391
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392 TABLE
EXERCISE
1. Physical n
F’FKD
7
CPTD HS
5 6
characteristics
&e,
PATHOPHYSIOLOGY
IN HUMAN
of subjects
yr
Height, cm
Weight, kg
Peak vo2, ml 9kg-’ 0min-’
27t6 25k4 27t2
166-t-6 NO-+4 173-t-4
58.1t6.1 63.31~5.4 61.lt4.1
14.Okl.6 31.124.3 35.6t1.4
Values are means t SE; n, no. of subjects. healthy subjects.
voz,
O2 uptake; HS,
the ability of these substrates to compensate, by normalizing oxidative metabolism and exercise performance, for the lack of access to both glycogen and glucose. During dynamic exercise in healthy humans, cardiac output increases 5-6 liters for each liter of increase in oxygen uptake (9, 11). Recent findings link the absence of muscle glycogen as an oxidizable substrate in patients with McArdle’s disease to an exaggerated twofold steeper than normal cardiac output slope (1, 23). Thus another goal of this study was to examine the relationship between availability of oxidizable substrate and regulation of O2 transport during exercise in PFKD. This was accomplished by comparing the slopes of increase in cardiac output and heart rate in relation to systemic 0, uptake 1) among PFKD patients, CTPD patients, and healthy subjects and 2) in PFKD patients under distinctly different conditions of substrate availability to working muscle. METHODS
Patients
and Subjects
Seven patients (four male and three female) with muscle PFKD were studied. Each had a typical lifelong history of premature fatigability and failed to increase blood lactate with ischemic forearm exercise. In three PFKD patients, an absence of phosphofructokinase was demonstrated biochemically in biopsied skeletal muscle. In three other PFKD patients, the diagnosis was established by an absence of the M isozyme of phosphofructokinase in erythrocytes. In one PFKD patient, the diagnosis was inferred from the presence of symptoms and laboratory findings identical to those of her brother, in whom the diagnosis of PFKD was biochemically proven. Also studied were five patients (two male and three female) with skeletal muscle CPTD and six healthy sedentary subjects (three male and three female). The CPTD patients had typical histories of intolerance to prolonged exercise exacerbated by fasting, exertional myoglobinuria, and CPTD measured biochemically in skeletal muscle (7). The healthy subjects did not participate in regular physical conditioning
for rl
yr before
the study. The PFKD patients, CPTD patients, and healthy subjects were similar (P > 0.05) in age, height, and weight (Table 1). None of the patients or subjects displayed clinical or electrocardiographic evidence of any cardiac abnormality or was taking any medication that might have af-
fected cardiac function. For all patients and healthy subjects, hemoglobin and hematocrit were in the nor-
MUSCLE
PFK DEFICIENCY
ma1 range. The research protocol was approved by the Institutional Review Board, and each patient and subjeet gave signed informed consent. Experiments The PFKD and CPTD patients and healthy subjects were studied at rest and during exercise 2-3 h postprandially after a normal mixed diet, i.e., control conditions. In four PFKD patients, rest and exercise measurements also were obtained under three additional conditions: lactate, during intravenous infusion of a l/5 normal sodium lactate solution at a rate of 8 ml/min over the duration of the experiment (1.5-2 h); fasting plus prolonged exercise, after a 12- to 14-h fast followed by 45 min of continuous exercise at a work rate equivalent to ~50% of peak exercise intensity; and glucose, during intravenous infusion of 10% dextrose at a rate of 6 ml/ min for 1.5-2 h. Under each condition, exercise was performed for 5-6 min at one or two submaximal work rates and at peak exercise intensity. For the control, lactate, and glucose experiments, the exercise periods were separated by 15-min rest periods. For the experiment after fasting plus prolonged exercise, the first exercise period began 15 min after the 45-min continu ous work bout, and exercise periods were separated by 3-min rest periods. The purpose of shorter rest periods under fasting plus prolonged exercise conditions was to maintain postexercise hyperemia and increased muscle free fatty acid (FFA) delivery (32). For each condition, work rates were accomplished in ascending order of intensity, and peak exercise for the patients and healthy subjects was established, by having the subject or patient exercise at progressively higher work rates, as the highest work rate each individual could perform for 25 min before stopping because of leg fatigue. In PFKD, frank muscle pain was virtually absent as a compl aint or exercise end point. PYoceduYes
All measurements were made with the patients and subjects in the sitting position. Resting data were obtained after 230 min of quiet sitting. Exercise was performed on a National Aeronautics and Space Administration Skylab pedal rate-independent cycle ergometer. Expired air was collected in Douglas bags at rest and in the last 2 min of each exercise work rate. Fractions of 02, COB, and Nz in expired air were determined with a P&kin-Elmer ilOOA mass spectrometer. Ventilation was measured with a Tissot spirometer, and Voz was calculated by m eans of standard formulas. Cardiac output was determ .ined at rest and in the last 15 s of each work rate with the version of the C&H, rebreathing technique developed by Triebwasser et al. (39), in which the patient rebreathes a gas mixture consisting of 45% O,8% He-0.7% C,H,-0.3% C180-46% N, from an anesthe-
sia bag. Helium serves as an indicator of system volume, and the rate of disappearance of C&H, from the system with respect to helium is proportional to pulmonary blood flow and cardiac output. At rest the patients and
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EXERCISE
PATHOPHYSIOLOGY
IN
subjects breathed with a “breath sounds” tape at a rate of 18 breaths/min. For measurement of exercise cardiac output, the patients and subjects were permitted to breathe at spontaneous rates. Gas concentrations were measured by a mass spectrometer (model llOOA, Perkin-Elmer). Mass spectrometer data were processed online by an LSI-11 minicomputer. Comparison of our C&H, technique with simultaneous indocyanine green measurements of cardiac output at rest and during submaximal and maximal exercise has established an absence of systematic error, a linear r of 0.94 + 0.6, and a standard error of estimate of ~5% (39). Details of the C2H, method have been published previously (26, 39). Heart rate was determined from continuous electrocardiographic tracings counting R-R intervals over 220 consecutive beats. Heart rate values from the last minute of each work rate were used in data analysis. An ElemaSchonander eight-channel recorder was used for continuous recording of heart rate and gas concentrations. Blood samples from the four PFKD patients studied under different conditions of substrate availability were obtained from an indwelling forearm venous catheter at rest and at the end of each work rate. Plasma FFA concentration was measured calorimetrically (20). Enzymatic assays were used to measure plasma glucose (Worthington Diagnostics) and blood lactate (12). Data Analysis Statistical analysis of the differences among the physiological data collected under control conditions for PFKD patients, CTPD patients, and healthy control subjects was accomplished by one-way analysis of variance (ANOVA) (40). For each PFKD patient, CPTD patient, and healthy subject, individual linear regression equations including data from rest and all exercise work rates were performed for the dependent variables, cardiac output and heart rate, on the independent variable, oxygen uptake. Statistical comparisons among the patient and subject groups were made by use of separate ANOVAs performed on each of three sets of data: data collected at rest, data consisting of the slopes of the individual linear regression equations, and data collected at maximal exercise. If an ANOVA indicated a significant F value for a given measurement or derived variable, a Newman-Keuls multiple comparison was used to test for specific intergroup differences (40). For all analyses, a difference was accepted as significant if P < 0.05. For each of the four PFKD patients studied under control conditions and during lactate infusion, fasting plus prolonged exercise, and glucose infusion, average concentrations of plasma FFA, plasma glucose, and blood lactate were calculated for each experimental condition by use of the corresponding rest and exercise data. Standard descriptive statistics were then used to calculate for a given condition the means t SE of the FFA, glucose, and lactate concentrations for the four PFKD patients. All data are presented as means t SE or individual values.
HUMAN
MUSCLE
PFK
DEFICIENCY
393
RESULTS
Comparisons Among PFKD and CPTD Patients Healthy Subjects Under Control Conditions
and
Rest data. Resting 0, uptake, systemic arteriovenous O2 difference, cardiac output, and heart rate were each similar (P > 0.05) among the patient and control groups (Fig. 1, A-D). Slope data. In the PFKD patients, cardiac output and heart rate each increased more than twofold more steeply (P c 0.001) in relation to 0, uptake than in CPTD patients and healthy subjects (Fig. 2, A and B). There was no significant difference in the slope of cardiac output or heart rate (P > 0.05) between the CPTD patients and healthy subjects. Peak exercise data. Peak exercise work rates were dramatically lower in the PFKD patients (23 t 6) than in the CPTD patients (142 t 33) or healthy subjects (171 t 17) (P < 0.001). Peak O2 uptake and arteriovenous O2 difference also were markedly lower (P < 0.001) in the PFKD patients (0.83 t 0.16 l/min and 7.1 t 0.5 ml/dl, respectively) than in the CPTD patients (2.03 + 0.40 l/ min and 15.0 t 0.8 ml/dl, respectively) or healthy subjects (2.34 t 0.24 l/min and 16.4 t 0.7 ml/dl, respectively); (Fig. 1, A and B). Peak cardiac output was similar (P > 0.05) in all three groups (Fig. 1C). In PFKD, peak exercise heart rate (155 t 3) was lower than in CPTD (183 t 8) or healthy subjects (186 t 3) (P < 0.001). There were no significant differences between healthy subjects and CPTD patients for any measurement or calculated variable at peak exercise. Comparisons Among Control Conditions, Lactate Infusion, Fasting Plus Prolonged Exercise, and Glucose Infusion in PFKD Patients Substrate data. For each of the four PFKD patients studied during modification of substrate availability, blood lactate was higher during lactate infusion than under control conditions [1.40 $- 0.34 vs. 0.95 t 0.04 (SE) mM, respectively]. Plasma glucose levels during glucose infusion (9.3 & 1.2 mM) were almost twofold those observed under the other treatments (control 5.2 t 0.4 mM, fasting plus prolonged exercise 4.9 t 0.2 mM, lactate infusion 4.8 t 0.2 mM). Plasma FFA levels during fasting plus prolonged exercise were in each patient higher than under control conditions or during glucose infusion [0.57 t 0.07,0.30 t 0.04, and 0.34 t 0.08 (SE) mM, respectively]. Rest data. Resting heart rate, cardiac output, arteriovenous oxygen difference, and 0, uptake were not altered in a consistent manner by any intervention. Slope data. For each PFKD patient, slopes of increase in cardiac output with respect to increasing 0, uptake were lower during infusion of lactate and after fasting plus prolonged exercise than under control conditions or during glucose infusion (Fig. 3A). Cardiac output slopes averaged 8.4 t 0.5, 8.6 t 0.9, 13.0 t 1.1, and 12.0 t 1.0 during lactate infusion, after fasting plus prolonged exercise, under control conditions, and during glucose infusion, respectively. The slope of increase in heart rate in relation to increasing O2 uptake was for each PFKD
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394
EXERCISE
PATHOPHYSIOLOGY
IN HUMAN
MUSCLE
PFK DEFICIENCY
~ PFKD
Healthy
CPTD
FIG. 1. Mean O2 uptake (A), arteriovenous O2 difference (B), cardiac output (C), and heart rate (D) at rest (open bars) and during peak exercise (hatched bars) in patients with muscle PFKD (n = 7) or CPTD (n = 5) and in healthy subjects (n = 6). *Significantly (P -c 0.001) lower peak exercise values for PFKD patients than for CPTD patients or healthy subjects.
patient lower during infusion of lactate than under control conditions or during glucose infusion (Fig. 3B). After fasting plus prolonged exercise, the heart rate slope was lower than under control conditions in all four PFKD patients and lower than during glucose infusion in three of four patients. Peak exercise data. For each PFKD patient, peak work rate, 0, uptake, and arteriovenous 0, difference were higher during intravenous lactate infusion and after fasting plus prolonged exercise than under control conditions or glucose infusion (Fig. 4, A-C). Peak work rate averaged 36 t 6 and 24 t 2 W with lactate infusion and fasting plus prolonged exercise and 16 t 3 and 13 t 2 W under control conditions and during glucose infusion, respectively. Peak 0, uptake averaged 1.04 t 0.10 and 0.84 t 0.03 l/m’ in with lactate infusion and fasting plus prolonged exercise and 0.70 t 0.07 and 0.63 & 0.05 l/min under control conditions and during glucose infusion, respectively. Peak arteriovenous 0, difference averaged 8.1 t 0.5 and 7.7 t 0.6 ml/d1 with lactate infusion and fasting plus prolonged exercise and 6.1 -t 0.2 and 5.5 t 0.2 ml/d1 under control conditions and during glucose infusion, respectively. In contrast, peak cardiac output was not markedly different among the four exercise conditions (Table 2). However, peak heart rate tended to be higher under control conditions and during lactate infusion than during glucose infusion or after fasting plus prolonged exercise.
DISCUSSION
The major findings of this study were a dramatically low peak work rate, 0, uptake, and systemic arteriovenous 0, difference in patients unable to metabolize muscle glycogen and blood glucose because of a defect in muscle glycolysis at the level of PFK. Peak work rate and 0, uptake achieved by the PFKD patients were, respectively, 13 and 35% of peak work rate and 0, uptake for the healthy subjects. The markedly reduced peak 0, uptake in the PFKD patients was not caused by a subnormal O2 delivery and was largely unrelated to a peak exercise heart rate 17% lower than that of healthy subjects. Peak cardiac output (i.e, 0, delivery) was similar to that of healthy control subjects. Preservation of a virtually normal peak cardiac output in PFKD indicates a normal cardiac pump performance and implies a sparing of the myocardium that is likely related to the presence of tissue-specific isozymes of phosphofructokinase (33). A low peak exercise heart rate in PFKD relates to potential risks of extreme exertion, including rhabdomyolysis, myoglobinuria, and possible renal failure, which largely preclude exhorting patients with muscle glycolytic defects to fully maximal effort under most exercise conditions. 00 2max for the PFKD patients can be estimated by extrapolation from their slope of linear regression of heart rate (beats/min) on 0, uptake (Vmin), which averaged 131. With a mean heart rate in maximal
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EXERCISE
PATHOPHYSIOLOGY
IN
131*16*
HUMAN
MUSCLE
PFK
395
DEFICIENCY
rate equivalent to -50% of VOzmax (10). In contrast to PFKD, patients with a selective impairment in longchain fatty acid oxidation due to CPTD and normal access to muscle glycogen and blood glucose as oxidative fuels had virtually normal peak work rate, 0, uptake, and arteriovenous O2 difference. These findings are consistent with evidence that access to carbohydrate fuel sources is required for normal 0, extraction by working muscle and normal expression of maximal aerobic power (15) and with the hypothesis that reduced availability of oxidizable substrate in the form of muscle glycogen and blood glucose is a major reason for the exercise intolerance characteristic of PFKD. The very low peak O2 uptake, markedly attenuated rise in arteriovenous 0, difference, and essentially norma1 peak cardiac output in PFKD patients are quantitatively similar to values reported for patients with McArdle’s disease (X), who lack access to muscle glycogen but not blood glucose as oxidizable substrates. This finding implies that lack of access to muscle glycogen per se, is the specific disturbance in fuel availability
0
. FIG. 2. Slopes of linear regressions of cardiac output (&) (A) and heart rate (HR) (B) on O2 uptake (Vo,) in patients with muscle PFKD (n = ‘7) or CPTD (8 = 5) and in healthy subjects (HS, n = 6). Values are means * SE. *Significantly steeper (P < 0.001) slopes for PFKD patients than for CPTD patients or HS.
exercise assumed to be similar to that of the agematched healthy subjects, i.e., 186 beats/min, mean vo 2max for the seven PFKD patients is estimated to be -240 ml/min higher than their mean measured peak 0, uptake of 0.83 l/min. With correction for body weight, the estimated value for voZmax in PFKD (18 ml. min-l . kg-‘) would be 50% that of the healthy subjects (36 ml 4min-l kg-l). In contrast to the typical approximately threefold increase (from 5.3 to 16.4 ml/dl) of arteriovenous 0, difference from rest to maximal exercise for the healthy sedentary controls, arteriovenous 0, difference only rose -60% from rest (4.5 ml/dl) to peak exercise (7.1 ml/dl) in PFKD. Thus the subnormal peak O2 uptake of the PFKD patients was due primarily to markedly attenuated peak arteriovenous 0, difference reflecting a subnormal capacity for muscle 0, extraction. in PFKD of -50% normal corresponds closely to the percentage of i702,,, achievable by ultramarathon runners after depletion of muscle glycogen related to several hours of running (6) and reinforces the notion that the virtually exclusive use of lipid as oxidizable substrate normally can sustain a metabolic
PFKD Patlents 0 SL l SG q RA
= OR
l
n
0 a 0
cl
l q
l
0
a
n
A~%nax
Lactate
Prolonged
GIUCOW
3. Individual values for slopes of linear regressions of cardiac output (&) (A) and heart rate (HR) (B) on 0, uptake (oo,> in patients with muscle PFKD (n = 4) under control conditions, during lactate infusion, after fasting followed by prolonged exercise, and during glucose infusion. FIG.
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396
EXERCISE
PATHOPHYSIOLOGY
IN HUMAN
MUSCLE
PFK DEFICIENCY
0 8
0 0 0
n El
Control
Lactate
Prolonged
Glucose
PFKD Patients 0 l 0 m
5
’
I
Control
I
Lactate
I
Prolonged
SL SG RA DR
I
Glucose
FIG, 4. Individual peak exercise values for work rate (A), O2 uptake (B), and arteriovenous 0, difference (C) in patients with muscle PFKD (n = 4) under control conditions, during lactate infusion, after fasting followed by prolonged exercise, and during glucose infusion.
primarily responsible for the impaired oxidative metabolism and associated exercise intolerance in PFKD. Supporting this conclusion are findings that -I) muscle glucose utilization normally accounts for only a low perqentage of total ATP production during exercise at vo 2max in healthy subjects (19) and Z) peak 0, uptake and arteriovenous 0, difference increased but remained abnormally low after glucose infusion in McArdle’s disease patients (15). Thus unavailability of glycogen to fuel oxidative metabolism normally makes phosphofructokinase-deficient muscle heavily dependent on oxidation of lipid fuels. Recent findings in healthy subjects are consistent with the view that the capacity of the systemic circulation for 0, delivery normally limits muscle oxidative
TABLE
2. Peak exercise data for PFKD Work
Control Lactate Post-pro1
W
l/min
16t,3
0.7O-tO.07 1.04+0.10 0.84t0.03 0.63+0.05
6.1t0.2 8.1*0.5 7.7kO.6 5.520.2
are means
systemic arteriovenous plus
prolonged
Cardiac a-v02 Diff, ml/d1
36+6 24t2 13+2
Glucose Values
qo,,
Rate,
exercise.
_t
patients
SE for 4 patients. Qo,, O2 difference; post-prol,
output, l/min
Heart Rate, beats/min
11.64t0.79 12.80&0.83 11.50t0.64 11.24+0.58
155al 159+3 144_t6 139&Z
O2 uptake; a-v& Diff, exercise after fasting
metabolism in large muscle exercise (34). In contrast, although we are unaware of measurements of muscle blood flow in PFKD, the normal peak cardiac output but low arteriovenous 0, difference in PFKD and the exaggerated limb blood flow in relation to work rate or 0, uptake in McArdle’s disease (24,30) support the conclusion that, in PFKD, muscle oxidative metabolism normally is not limited by 0, delivery. Results of interventions to increase availability of oxidizable substrate instead imply that rates of delivery and/or extraction of blood-borne oxidizable substrates normally are involved in limiting muscle oxidative metabolism in PFKD. These interventions consisted of providing substrates that bypass the metabolic defect at PFKD: 1) lactate, which serves as a source of pyruvate, the substrate required for maximal oxidative metabolism (lo), and 2) FFA. In PFKD, increasing availability of lactate via intravenous infusion increased peak exercise work rate more than twofold and peak O2 uptake and arteriovenous O2 difference by 48 and 3376, respectively. Experimental support for enhancement of exercise performance by lactate oxidation derives from findings that contraction of isolated muscle treated with the glycolytic inhibitor iodoacetate persisted considerably longer in the presence of 0, and lactate than in the presence of 0, alone (29). Findings in healthy human subjects are compatible with an important role for oxidation by working muscle of lactate infused or produced during exercise (2).
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EXERCISE
PATHOPHYSIOLOGY
IN
HUMAN
MUSCLE
PFK
DEFICIENCY
397
In comparison with control conditions, the intervension of working muscle and enhances delivery of oxidiztion involving overnight fasting and prolonged exercise able substrate when substrate availability limits muscle increased plasma FFA almost twofold and peak exercise 0, extraction. Mechanisms for the exaggerated cardiac work rate, 0, uptake, and arteriovenous 0, difference an output slope likely include increased activation of medulaverage of 53, 20, and 260/c, respectively. Delivery of lary cardiovascular centers by impulses originating in FFA is a function of blood flow to active muscle and I) higher motor control areas in association with volunplasma FFA concentration. Because peak cardiac outtary motor effort, i.e., “central command,” and 2) thinly put after fasting and prolonged exercise was very simimyelinated and unmyelinated group III and IV skeletal lar to that under control conditions, the increased muscle afferents sensitive to stimuli related to muscle plasma FFA, peak 0, uptake, and arteriovenous 0, difenergy metabolism (37). The augmented cardiac output ference after fasting plus prolonged exercise implies response of the McArdle’s disease patients studied by that muscle oxidative metabolism in PFKD normally is Braakhekke et al. (la) could be interpreted to relate to limited in part by the rate of FFA delivery related to the an increased central command associated with muscle rate of FFA mobilization from adipose tissue. However, fatigue; however, a normal cardiac output-O, uptake repeak 0, uptake was not fully normalized by fasting plus lationship persists in healthy subjects during severe faprolonged exercise, and it is likely that other factors, tiguing effort (36). Normal cardiac output slopes in pasuch as the rate of extraction of plasma FFA by active tients with weakness due to muscular dystrophy (14) muscle, intramuscular triglyceride lipolysis, and the imply that an increased voluntary motor effort assorate of mitochondrial oxidation of FFA, limit the con- ciated with weakness of rested muscle that is present tribution of lipid substrates to oxidative metabolism in infrequently in PFKD (33) is not responsible for the exPFKD. aggerated cardiac output slope in PFKD. It has been In PFKD, although resting cardiac output was norargued (22) that steeper than normal cardiac output mal, there was an exaggerated slope of increase in car- slopes in McArdle’s disease primarily relate to augdiac output (l/min) with respect to 0, uptake (Vmin) mented activation of the muscle afferents with respect from rest to exercise. The normal 0, content of arterial to work or metabolic rate by an error signal originating blood is ~200 ml/l. Thus to increase 0, transport by 1 in active muscle associated with an exaggerated decline liter, cardiac output must increase by -5 liters. In in the muscle phosphorylation potential, [ATP]/ healthy human subjects, the slope of increase of cardiac [ADP][PJ, which is a quantitative expression of the caoutput on 0, uptake ranges from 4.6 to 6.3 with minor respiration and and inconsistent differences with respect to age, sex, pacity or potential for mitochondrial oxidative phosphorylation (4). However, inorganic body weight, and level of physical conditioning (cf. 9, 11), reflecting a normal, -1:l coupling of systemic O2 phosphate fails to rise normally in active phosphofructokinase-deficient muscle (8), and recent findings (1) transport and utilization (26). In contrast, a cardiac outsuggest that a subnormal [ATP]/[ADP] or simply an exput slope >11 in PFKD indicates a gross mismatch beaggerated accumulation of [ADP] may be a metabolic tween 0, transport and utilization specific to exercise. error signal common to phosphofructokinaseand phosNormal cardiac output slopes in patients with CPTD phorylase-deficient muscle. support the view that an exaggerated 0, transport reThe precise physiological and biochemical factors sponse to exercise in PFKD is not a general consequence likely to link subnormal muscle [ATP]/[ADP] or exagof abnormal muscle energy metabolism but relates gerated muscle [ADP] with augmented activation of closely to the virtually complete unavailability of oxidagroup III and IV muscle afferents are poorly undertive substrate in the form of glycogen, the primary intramuscular fuel. Consistent with this conclusion is the ex- stood. Nevertheless, evidence supporting reduced muscle ADP accumulation (22) in association with improved aggerated cardiac output slope of patients with vir0, extraction and normalization of cardiac output slope tually absent glycogenolysis due to McArdle’s disease during interventions to increase availability of oxidiz(la, 14, 23) and the essentially normal cardiac output able substrate in both PFKD and McArdle’s disease imslope and more normal peak 0, uptake in patients with between muscle oxidative glycogen-debranching enzyme deficiency (17,25), whose plies a close relationship phosphorylation and regulation of 0, transport. Experimuscles can oxidize a limited number of glucosyl units mental support for involvement of the muscle afferents from the outer branches of the glycogen molecule derives from findings linking reflex increases in cardiac through the normal action of phosphorylase (3). Partial in anesthenormalization of the exaggerated cardiac output slope output to muscle oxidative phosphorylation impaired muscle in PFKD during interventions to increase availability of tized animals (27). In experimentally oxidative phosphorylation and 0, extraction, blood flow alternative blood-borne oxidizable substrates, either lactate or FFA, supports this line of reasoning. In con- and cardiac output are exaggerated with respect to mettrast, no such normalization of cardiac output slope re- abolic rate (28,31), and there is a close inverse relationsulted from infusion of glucose, a substrate that cannot ship between blood flow and the ratio of [ATP] to its hydrolysis products (31). Recent findings of an exaggerbe oxidized by PFK-deficient muscle. Increases in peak 0, extraction accompanying parated 0, transport relative to metabolic rate in patients with defective muscle oxidative metabolism involving tially normalized cardiac output slopes in connection the mitochondrial respiratory chain (16) and citric acid with lactate infusion or fasting plus prolonged exercise in PFKD are compatible with the hypothesis that an cycle (13) are consistent with the hypothesis that norexaggerated cardiac output response augments perfumal oxidative phosphorylation in active muscle is cruDownloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (128.059.222.107) on January 16, 2019.
398
EXERCISE
PATHOPHYSIOLOGY
cial for the normal coupling of 0, delivery zation in exercising humans.
IN HUMAN
and 0, utili-
The technical assistance of Karen Aayad, Marguerite Gunder, Paul Gustafson, Julius Lamar, and Willie E. Moore, Jr,, is gratefully acknowledged. We thank Dr. Gunnar Blomqvist for support and Dr. Salvatore DiMauro, Department of Neurology, Columbia University College of Physicians and Surgeons, for patient referrals. This research was supported by National Institutes of Health Grants HL-06296 and MOl-RR-00633, the Department of Veterans Affairs, the Muscular Dystrophy Association, and the Harry S. Moss Heart Center. S. F. Lewis is the recipient of Research Career Development Award HL-01581. Address for reprint requests: S. F. Lewis, Dept. of Health Sciences, Boston University, 635 Commonwealth Ave., Boston, MA 02215. Received 23 April 1990; accepted in final form 22 August 1990. REFERENCES
1. BERTOCCI, L., R. G. HALLER, S. F. LEWIS, JI L. FLECKENSTEIN, AND R. L. NUNNALLY. Abnormal high-energy phosphate metabolism in human muscle PFK deficiency. J. AppZ. Physiol. In press. Ia.BRAAKHEKKE, J. P., M, I. DEBRUIN, D. F. STEGEMAN, R. A. WEVERS, R. A. BINKHORST, AND E. M. JOOSTEN, The second wind phenomenon in McArdle’s disease. Brain 109: 1087-1101,1986. 2. BROOKS, G. A. The lactate shuttle during exercise and recovery. Med. Sci. Sports Exercise 18: 360-368,1989. 3. BROWN, D. H. Glycogen metabolism and glycolysis in muscle. In: Myology, edited by A. G. Engel and B. Q. Banker. New York: McGraw-Hill, 1986, p. 1603-1617. 4. CHANCE, B. Applications of “P NMR to clinical biochemistry. Ann. NYAcad.
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7. DIMAURO, S., AND A. PAPADIMITRIOU. Carnitine palmitoyltransferase deficiency. In: Myology, edited by A. G. Engle and B. Q. Banker. New York: McGraw-Hill, 1986, p. 1697-1708. 8. EDWARDS, R. H. T., D. R. WILKIE, M. J. DAWSON, R. E. GORDON, AND D. SHAW. Clinical use of nuclear magnetic resonance in the investigation of myopathy. Lancet 1: 725-730,1982. 9. FAUL~ER, J. A., G. F. HEIGENHAUSER, AND M. A. SCHORK. The cardiac output-oxygen uptake relationship of men during graded bicycle ergometry. Med. Sci. Sports 9: 148-154, 1977. 10. GOLLNICK, P. D. Metabolism of substrates: energy substrate metabolism during exercise and as modified by training. Federation Proc. 44: 353-357,1985. 11. GRANDE, F., AND H. L. TAYLOR. Adaptive changes in the heart, vessels, and patterns of control under chronically high loads. In: Handbook of Physiology. CircuZatiun. Washington, DC: Am. Physiol. Sot., 1965, sect. 2, vol. II, p. 2615-2677. 12. GUTMANN, I., AND A. W. WA~EFELD. L-(+)Lactate. Determination with lactate dehydrogenase and NAD. In: Methods of Enxymatic Analysis (2nd ed.), edited by H. U. Bergmeyer. New York: Academic, 1974, p. 1464-1468. 13. HALLER, R. G., K. G. HENRIKSSON, L. JORFELDT, N.-H. ARESKOG, AND S. F. LEWIS. Muscle succinate dehydrogenase deficiency: exercise pathophysiology of a novel mitochondrial myopathy (Abstract). NeuroZogy 40, SuppZ I: 413, 1990. 14, HALLER, R. G., S. F. LEWIS, J. D. COOK, AND C. G. BLOMQVIST. Hyperkinetic circulation during exercise in neuromuscular diseases. Neurology 33: 1283-1287,1983. 15. HALLER, R. G., S. F. LEWIS, J. D. COOK, AND C. G. BLOMQVIST. Myophosphorylase deficiency impairs muscle oxidative metabolism. Ann. Neural. 17: 196-199,1985. 16. HALLER, R. G., S. F. LEWIS, R. W. ESTABROOK, S. DIMAURO, S. SERVIDEI, AND D. W. FOSTER. Exercise intolerance, lactic acidosis, and abnormal cardiopulmonary regulation in exercise associated with adult skeletal muscle cytochrome c oxidase deficiency. J. C&x. Invest.
84: 155-161,
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HARTWIG, G. B., N. E. LEATHERMAN, W. P. MCNEIL, AND J. KYLSTRA. Exercise performance in debrancher deficiency myopathy. Trans. Am. Neural. Assoc. 104: 248-252,1979. 18. HERMANSEN, L., E. HULTMAN, AND B. SALTIN. Muscle glycogen during prolonged severe exercise. Acta Physiok Stand. 71: 129-139,
1967. 19. KATZ, A., S, BROBERG, K. SAHLIN, AND J. WARREN. Leg glucose uptake during maximal dynamic exercise in humans. Am. J. PhysioL 251 (Endocrinol. Metab. 14): E65-E70, 1986. 20. LAUWERYS, R. R. Calorimetric determination of free fatty acids. Anal. Biochem. 32: 331-333,1969. 21. LEWIS, S. F., AND R. G. HALLER. The pathophysiology of McArdle’s disease: clues to regulation in exercise and fatigue. J. AppZ. Physiol. 61: 391-401, 1986. 22. LEWIS, S. F., AND R. G. HALLER. Disorders of muscle glycogenolysis/glycolysis: the consequences of substrate-limited oxidative metabolism in humans. In: Biochemistry of Exercise VII, edited by A. W. Taylor, P. D. Gollnick, H. J. Green, C. D. Inanuzzo, E. G, Noble, G. Metivier, and J. R. Sutton. Champaign, IL: Human Kinetics, 1990, p. 211-226. 23. LEWIS, S. F., R. G. HALLER, J. D. COOK, AND C. G. BLOMQVIST. Metabolic control of cardiac output response to exercise in McArdle’s disease. J. AppZ. Physiol. 57: 1749-1753,1984. 24. LEWIS, S., R. HALLER, K. G. HENRIKSSON, N.-H. ARESKOG, AND L. JORFELDT. Availability of oxidative substrate and leg blood flow during exercise in McArdle’s disease (Abstract). Federation Proc. 45: 783, 1986. 25. LEWIS, S. F., M. G. TANSEY, AND R. G. HALLER. Dependency of cardiac output on substrate supply in muscle glycogen storage diseases (Abstract). Med. Sci. Sports Exercise 19, Supple: S55,1987. 26. LEWIS, S. F., W. F. TA~OR, R. M. GRAHAM, W. A. PETTINGER, J. E. SCHUTTE, AND C. G. BLOMQVIST. Cardiovascular responses to exercise as functions of absolute and relative workload. J. AppZ. Physiol. 54: 1314-1323, 1983. 27. LIANG, C-S., AND W. B. HOOD, JR. Afferent neural pathway in the regulation of cardiopulmonary responses to tissue hypermetabolism. Circ. Res. 38: 209-214, 1976. 28. LIANG, C.-S., AND W. E. HUCKABEE. Mechanisms regulating the cardiac output response to cyanide infusion, a model of hypoxia. J. CZin. Invest.
52: 311%3128,1973.
29. MAWSON, C. A. The lactic acid metabolism of frog’s muscle poisoned with iodoacetic acid. J. Physiol. Land, 75: 201-212, 1932. 30. MCARDLE, B. Myopathy due to a defect in muscle glycogen breakdown. Clin. Sci. Land. IO: 13-33, 1951. 31. NUUTINEN, E. M., K. NISHIKI, M. ERECINSKA, AND D. F. WILSON. Role of mitochondrial oxidative phosphorylation in regulation of coronary blood flow. Am. J. Physiol. 243 (Heart Circ. PhysioZ. 12): H159-Hl69,1982.
32. PERNOW, B. B., R. J. HAVEL, AND D. B. JENNINGS. The second wind phenomenon in McArdle’s syndrome. Acta Med. Scand. 472: 294307,1967. 33. ROWLAND, L., S. DIMAURO, AND R. LAYZER. Phosphofructokinase deficiency. In: MyoZogy, edited by A. G. Engel and B. Q. Banker. New York: McGraw-Hill, 1986, p. 1603-1617. 34. SALTIN, B. Capacity of blood flow delivery to exercising skeletal muscle in humans. Am. J Cardiol. 62: 30E-35E, 1988. 35. SALTIN, B., AND J. KARLSSON. Muscle glycogen utilization during work of different intensities. In: Muscle Metabolism During Exercise, edited by B. Pernow and B. Saltin. New York: Plenum, 1971, p. 289-299. 36. SALTIN, B., AND J. STENBERG. Circulatory response to prolonged severe exercise. J. Apple Physiol. 19: 833-838,1964. 37. SHEPHERD, J. T., C. G. BLOMQVIST, A. R. LIND, J. H. MITCHELL, AND B. SALTIN. Static (isometric) exercise. Retrospection and introspection. Circ. Res. 48, Supph I: 179-188,198l. 38. TARUI, S., G. OKUNO, Y. IKURA, T. TANAKA, M. SUDA, AND M. NISHIKAWA. Muscle phosphofructokinase deficiency in skeletal muscle: a new type of glycogenosis. Biochem. Biophys. Res. Commun. 19: 571-523,1965.
39. TRIEBWASSER, J. H., R. L. JOHNSON, JR., R. P. BURPO, J. C. CAMPBELL, W. C. REARDON, AND C. G. BLOMQVIST. Noninvasive determination of cardiac output by a modified acetylene rebreathing procedure utilizing mass spectrometer measurements, Aviat. Space Environ.
Med.
48: 203-209,1977.
Principles in Experimental 40. WINER, B. J. Statistical ed.). New York: McGraw-Hill, 1971.
Design
(2nd
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LEWIS, SHOBHANA VORAj-, AND RONALD G. HALLER of Physiology and Neurology, University of Texas Southwestern Medical Center, Veterans Aflairs Medical Center, Dallas, Texas 75,216; and Scripps Clinic Foundation, La Jolla, CaLifbrnia 92037
LEWIS, STEVEN F., SHOBHANA VORA, AND RONALD G. HALLER. Abnormal uxidative metabolism and O2 transport in muscle phosphofructokinase deficiency. J. Appl. Physiol. 70(1): 391-398, 1991.-Humans who lack availability of carbohydrate fuels may provide important models for the study of physiological control mechanisms. We compared seven patients who had unavailability of muscle glycogen and blood glucoseas oxidative fuels due to musclephosphofructokinase deficiency (PFKD) with five patients who had a selective defect in long-chain fatty acid oxidation due to carnitine palmitoyltransferase deficiency (CPTD) and with six healthy subjects. Peak cycle exercisework rate, peak 0, uptake (vo2), and arteriovenous O2difference were markedly lower (P < 0.001) for PFKD patients (23 t 6 W, 14 t 2 ml min-’ kg-l, and 7.1+ 0.5 ml/dl, respectively) than for CPTD patients (142 & 33 W, 31 t 4 ml min-’ kg-‘, and 15.0 ? 0.8 ml/dl, respectively) or healthy subjects (171 t 17 W, 36 t I ml min-’ kg;‘, and 16.4t 0.7 ml/d& respectively). Peak cardiac output (Q) was sim.ilar (P > 0.05) in all three groups, but the slopeof increase in Q (l/min) on 00, (l/min) from rest to exercise (At@Avo,) was more than twofold greater (P < 0.001)for PFKD patients (11.2 t 1.2) than for CPTD patients (4.6 & 0.6) and healthy subjects (4.6 t 0.2). Increasing availability of blood-borne oxidative substrates capable of metabolically bypassing the defect at phosphofructokinase (by fasting plus prolonged moderate exercise to increaseplasmafree tatty acids or by iv lactate infusion) increasedpeak work rate, VO,, and arteriovenous O2 difference, lacked consistent effect on peak &, and normalized Ag/Avoz in PFKD patients. The results extend our previous observations in patients with a block in muscle glycogen but not blood glucose oxidation due to phosphorylase deficiency and imply that specificunavailability of muscleglycogen asan oxidizable fuel is primarily responsible for abnormal muscle oxidative metabolism and associatedexercise intolerance and exaggerated AQ/Avo, in musclePFKD. The findings also endorse the concept that factors closely linked with muscleoxidative phosphorylation participate in regulating A&/A%,, likely via activation of metabolically sensitive muscle afferents. l
l
l
l
l
l
glycogen storage disease;carnitine palmitoyltransferase deficiency; oxygen uptake; cardiac output; arteriovenous oxygen difference; exercise performance; fasting; lactate infusion; free fatty acids; energy metabolism
THE IMPORTANCE
as fuels for human
of muscle glycogen and blood glucose exercise performance is well docu-
t S. Vora is deceased. OMI-7567/91
mented, but their physiological significance is incompletely understood. Studies performed in the late 1960s and early 1970s (l&35) showed a direct relationship between initial glycogen content in active muscle and duration of exercise performance at work rates corresponding to 7545% of maximal O2 uptake (VOW,,,). The classic experiments of Christensen and Hansen (5) demonstrated that the point of exhaustion in exercise lasting 3-6 h closely correlated with a subnormal blood glucose and symptoms of hypoglycemia. There is, however, very limited information on the impact of a virtually complete lack of access to carbohydrate fuels on regulatory mechanisms during exercise in humans. Recent findings in patients with absent glycogen breakdown due to myophosphorylase deficiency (type V glycogen storage disease or McArdle’s disease) suggest that human glycolytic disorders may provide unique experimental models in exercise and fatigue (21). In phos-
phofructokinase deficiency (PFKD; type VII glycogen storage disease), muscle glycogen and blood glucose are unavailable to fuel muscle contraction because they enter glycolysis proximal to the glycolytic block. This results in a striking failure of blood lactate to increase during ischemic exertion in patients with PFKD (33,38), spawning the conventional belief that the exercise intolerance of PFKD primarily relates to defective anaerobic energy supply. However, oxidative phosphorylation normally is the dominant mode of ATP resynthesis supporting the dynamic muscle contractions that compose most common physical activities. As an initial step in defining human PFKD as an experimental model, a major goal of the present study was to determine how unavailability of both muscle glycogen and blood glucose affects oxidative metabolism and exercise performance in patients with PFKD. This was accomplished by comparing peak 0, uptake, its components, cardiac output (reflecting 0, delivery) and arteriovenous oxygen difference (reflecting muscle 0, extraction), and peak exercise workload in patients with PFKD, patients with normal access to muscle glycogen and blood glucose as oxidative fuels but a selective defect in long-chain fatty acid oxidation due to muscle carnitine palmitoyltransferase deficiency (CPTD), and healthy control subjects. In addition, in PFKD patients, interventions designed to increase availability of oxidative substrates capable of metabolically bypassing the defect at phosphofructokinase were used to determine
$1.50 Copyright 0 1991the American
Physiological
Society
391
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392 TABLE
EXERCISE
1. Physical n
F’FKD
7
CPTD HS
5 6
characteristics
&e,
PATHOPHYSIOLOGY
IN HUMAN
of subjects
yr
Height, cm
Weight, kg
Peak vo2, ml 9kg-’ 0min-’
27t6 25k4 27t2
166-t-6 NO-+4 173-t-4
58.1t6.1 63.31~5.4 61.lt4.1
14.Okl.6 31.124.3 35.6t1.4
Values are means t SE; n, no. of subjects. healthy subjects.
voz,
O2 uptake; HS,
the ability of these substrates to compensate, by normalizing oxidative metabolism and exercise performance, for the lack of access to both glycogen and glucose. During dynamic exercise in healthy humans, cardiac output increases 5-6 liters for each liter of increase in oxygen uptake (9, 11). Recent findings link the absence of muscle glycogen as an oxidizable substrate in patients with McArdle’s disease to an exaggerated twofold steeper than normal cardiac output slope (1, 23). Thus another goal of this study was to examine the relationship between availability of oxidizable substrate and regulation of O2 transport during exercise in PFKD. This was accomplished by comparing the slopes of increase in cardiac output and heart rate in relation to systemic 0, uptake 1) among PFKD patients, CTPD patients, and healthy subjects and 2) in PFKD patients under distinctly different conditions of substrate availability to working muscle. METHODS
Patients
and Subjects
Seven patients (four male and three female) with muscle PFKD were studied. Each had a typical lifelong history of premature fatigability and failed to increase blood lactate with ischemic forearm exercise. In three PFKD patients, an absence of phosphofructokinase was demonstrated biochemically in biopsied skeletal muscle. In three other PFKD patients, the diagnosis was established by an absence of the M isozyme of phosphofructokinase in erythrocytes. In one PFKD patient, the diagnosis was inferred from the presence of symptoms and laboratory findings identical to those of her brother, in whom the diagnosis of PFKD was biochemically proven. Also studied were five patients (two male and three female) with skeletal muscle CPTD and six healthy sedentary subjects (three male and three female). The CPTD patients had typical histories of intolerance to prolonged exercise exacerbated by fasting, exertional myoglobinuria, and CPTD measured biochemically in skeletal muscle (7). The healthy subjects did not participate in regular physical conditioning
for rl
yr before
the study. The PFKD patients, CPTD patients, and healthy subjects were similar (P > 0.05) in age, height, and weight (Table 1). None of the patients or subjects displayed clinical or electrocardiographic evidence of any cardiac abnormality or was taking any medication that might have af-
fected cardiac function. For all patients and healthy subjects, hemoglobin and hematocrit were in the nor-
MUSCLE
PFK DEFICIENCY
ma1 range. The research protocol was approved by the Institutional Review Board, and each patient and subjeet gave signed informed consent. Experiments The PFKD and CPTD patients and healthy subjects were studied at rest and during exercise 2-3 h postprandially after a normal mixed diet, i.e., control conditions. In four PFKD patients, rest and exercise measurements also were obtained under three additional conditions: lactate, during intravenous infusion of a l/5 normal sodium lactate solution at a rate of 8 ml/min over the duration of the experiment (1.5-2 h); fasting plus prolonged exercise, after a 12- to 14-h fast followed by 45 min of continuous exercise at a work rate equivalent to ~50% of peak exercise intensity; and glucose, during intravenous infusion of 10% dextrose at a rate of 6 ml/ min for 1.5-2 h. Under each condition, exercise was performed for 5-6 min at one or two submaximal work rates and at peak exercise intensity. For the control, lactate, and glucose experiments, the exercise periods were separated by 15-min rest periods. For the experiment after fasting plus prolonged exercise, the first exercise period began 15 min after the 45-min continu ous work bout, and exercise periods were separated by 3-min rest periods. The purpose of shorter rest periods under fasting plus prolonged exercise conditions was to maintain postexercise hyperemia and increased muscle free fatty acid (FFA) delivery (32). For each condition, work rates were accomplished in ascending order of intensity, and peak exercise for the patients and healthy subjects was established, by having the subject or patient exercise at progressively higher work rates, as the highest work rate each individual could perform for 25 min before stopping because of leg fatigue. In PFKD, frank muscle pain was virtually absent as a compl aint or exercise end point. PYoceduYes
All measurements were made with the patients and subjects in the sitting position. Resting data were obtained after 230 min of quiet sitting. Exercise was performed on a National Aeronautics and Space Administration Skylab pedal rate-independent cycle ergometer. Expired air was collected in Douglas bags at rest and in the last 2 min of each exercise work rate. Fractions of 02, COB, and Nz in expired air were determined with a P&kin-Elmer ilOOA mass spectrometer. Ventilation was measured with a Tissot spirometer, and Voz was calculated by m eans of standard formulas. Cardiac output was determ .ined at rest and in the last 15 s of each work rate with the version of the C&H, rebreathing technique developed by Triebwasser et al. (39), in which the patient rebreathes a gas mixture consisting of 45% O,8% He-0.7% C,H,-0.3% C180-46% N, from an anesthe-
sia bag. Helium serves as an indicator of system volume, and the rate of disappearance of C&H, from the system with respect to helium is proportional to pulmonary blood flow and cardiac output. At rest the patients and
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EXERCISE
PATHOPHYSIOLOGY
IN
subjects breathed with a “breath sounds” tape at a rate of 18 breaths/min. For measurement of exercise cardiac output, the patients and subjects were permitted to breathe at spontaneous rates. Gas concentrations were measured by a mass spectrometer (model llOOA, Perkin-Elmer). Mass spectrometer data were processed online by an LSI-11 minicomputer. Comparison of our C&H, technique with simultaneous indocyanine green measurements of cardiac output at rest and during submaximal and maximal exercise has established an absence of systematic error, a linear r of 0.94 + 0.6, and a standard error of estimate of ~5% (39). Details of the C2H, method have been published previously (26, 39). Heart rate was determined from continuous electrocardiographic tracings counting R-R intervals over 220 consecutive beats. Heart rate values from the last minute of each work rate were used in data analysis. An ElemaSchonander eight-channel recorder was used for continuous recording of heart rate and gas concentrations. Blood samples from the four PFKD patients studied under different conditions of substrate availability were obtained from an indwelling forearm venous catheter at rest and at the end of each work rate. Plasma FFA concentration was measured calorimetrically (20). Enzymatic assays were used to measure plasma glucose (Worthington Diagnostics) and blood lactate (12). Data Analysis Statistical analysis of the differences among the physiological data collected under control conditions for PFKD patients, CTPD patients, and healthy control subjects was accomplished by one-way analysis of variance (ANOVA) (40). For each PFKD patient, CPTD patient, and healthy subject, individual linear regression equations including data from rest and all exercise work rates were performed for the dependent variables, cardiac output and heart rate, on the independent variable, oxygen uptake. Statistical comparisons among the patient and subject groups were made by use of separate ANOVAs performed on each of three sets of data: data collected at rest, data consisting of the slopes of the individual linear regression equations, and data collected at maximal exercise. If an ANOVA indicated a significant F value for a given measurement or derived variable, a Newman-Keuls multiple comparison was used to test for specific intergroup differences (40). For all analyses, a difference was accepted as significant if P < 0.05. For each of the four PFKD patients studied under control conditions and during lactate infusion, fasting plus prolonged exercise, and glucose infusion, average concentrations of plasma FFA, plasma glucose, and blood lactate were calculated for each experimental condition by use of the corresponding rest and exercise data. Standard descriptive statistics were then used to calculate for a given condition the means t SE of the FFA, glucose, and lactate concentrations for the four PFKD patients. All data are presented as means t SE or individual values.
HUMAN
MUSCLE
PFK
DEFICIENCY
393
RESULTS
Comparisons Among PFKD and CPTD Patients Healthy Subjects Under Control Conditions
and
Rest data. Resting 0, uptake, systemic arteriovenous O2 difference, cardiac output, and heart rate were each similar (P > 0.05) among the patient and control groups (Fig. 1, A-D). Slope data. In the PFKD patients, cardiac output and heart rate each increased more than twofold more steeply (P c 0.001) in relation to 0, uptake than in CPTD patients and healthy subjects (Fig. 2, A and B). There was no significant difference in the slope of cardiac output or heart rate (P > 0.05) between the CPTD patients and healthy subjects. Peak exercise data. Peak exercise work rates were dramatically lower in the PFKD patients (23 t 6) than in the CPTD patients (142 t 33) or healthy subjects (171 t 17) (P < 0.001). Peak O2 uptake and arteriovenous O2 difference also were markedly lower (P < 0.001) in the PFKD patients (0.83 t 0.16 l/min and 7.1 t 0.5 ml/dl, respectively) than in the CPTD patients (2.03 + 0.40 l/ min and 15.0 t 0.8 ml/dl, respectively) or healthy subjects (2.34 t 0.24 l/min and 16.4 t 0.7 ml/dl, respectively); (Fig. 1, A and B). Peak cardiac output was similar (P > 0.05) in all three groups (Fig. 1C). In PFKD, peak exercise heart rate (155 t 3) was lower than in CPTD (183 t 8) or healthy subjects (186 t 3) (P < 0.001). There were no significant differences between healthy subjects and CPTD patients for any measurement or calculated variable at peak exercise. Comparisons Among Control Conditions, Lactate Infusion, Fasting Plus Prolonged Exercise, and Glucose Infusion in PFKD Patients Substrate data. For each of the four PFKD patients studied during modification of substrate availability, blood lactate was higher during lactate infusion than under control conditions [1.40 $- 0.34 vs. 0.95 t 0.04 (SE) mM, respectively]. Plasma glucose levels during glucose infusion (9.3 & 1.2 mM) were almost twofold those observed under the other treatments (control 5.2 t 0.4 mM, fasting plus prolonged exercise 4.9 t 0.2 mM, lactate infusion 4.8 t 0.2 mM). Plasma FFA levels during fasting plus prolonged exercise were in each patient higher than under control conditions or during glucose infusion [0.57 t 0.07,0.30 t 0.04, and 0.34 t 0.08 (SE) mM, respectively]. Rest data. Resting heart rate, cardiac output, arteriovenous oxygen difference, and 0, uptake were not altered in a consistent manner by any intervention. Slope data. For each PFKD patient, slopes of increase in cardiac output with respect to increasing 0, uptake were lower during infusion of lactate and after fasting plus prolonged exercise than under control conditions or during glucose infusion (Fig. 3A). Cardiac output slopes averaged 8.4 t 0.5, 8.6 t 0.9, 13.0 t 1.1, and 12.0 t 1.0 during lactate infusion, after fasting plus prolonged exercise, under control conditions, and during glucose infusion, respectively. The slope of increase in heart rate in relation to increasing O2 uptake was for each PFKD
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394
EXERCISE
PATHOPHYSIOLOGY
IN HUMAN
MUSCLE
PFK DEFICIENCY
~ PFKD
Healthy
CPTD
FIG. 1. Mean O2 uptake (A), arteriovenous O2 difference (B), cardiac output (C), and heart rate (D) at rest (open bars) and during peak exercise (hatched bars) in patients with muscle PFKD (n = 7) or CPTD (n = 5) and in healthy subjects (n = 6). *Significantly (P -c 0.001) lower peak exercise values for PFKD patients than for CPTD patients or healthy subjects.
patient lower during infusion of lactate than under control conditions or during glucose infusion (Fig. 3B). After fasting plus prolonged exercise, the heart rate slope was lower than under control conditions in all four PFKD patients and lower than during glucose infusion in three of four patients. Peak exercise data. For each PFKD patient, peak work rate, 0, uptake, and arteriovenous 0, difference were higher during intravenous lactate infusion and after fasting plus prolonged exercise than under control conditions or glucose infusion (Fig. 4, A-C). Peak work rate averaged 36 t 6 and 24 t 2 W with lactate infusion and fasting plus prolonged exercise and 16 t 3 and 13 t 2 W under control conditions and during glucose infusion, respectively. Peak 0, uptake averaged 1.04 t 0.10 and 0.84 t 0.03 l/m’ in with lactate infusion and fasting plus prolonged exercise and 0.70 t 0.07 and 0.63 & 0.05 l/min under control conditions and during glucose infusion, respectively. Peak arteriovenous 0, difference averaged 8.1 t 0.5 and 7.7 t 0.6 ml/d1 with lactate infusion and fasting plus prolonged exercise and 6.1 -t 0.2 and 5.5 t 0.2 ml/d1 under control conditions and during glucose infusion, respectively. In contrast, peak cardiac output was not markedly different among the four exercise conditions (Table 2). However, peak heart rate tended to be higher under control conditions and during lactate infusion than during glucose infusion or after fasting plus prolonged exercise.
DISCUSSION
The major findings of this study were a dramatically low peak work rate, 0, uptake, and systemic arteriovenous 0, difference in patients unable to metabolize muscle glycogen and blood glucose because of a defect in muscle glycolysis at the level of PFK. Peak work rate and 0, uptake achieved by the PFKD patients were, respectively, 13 and 35% of peak work rate and 0, uptake for the healthy subjects. The markedly reduced peak 0, uptake in the PFKD patients was not caused by a subnormal O2 delivery and was largely unrelated to a peak exercise heart rate 17% lower than that of healthy subjects. Peak cardiac output (i.e, 0, delivery) was similar to that of healthy control subjects. Preservation of a virtually normal peak cardiac output in PFKD indicates a normal cardiac pump performance and implies a sparing of the myocardium that is likely related to the presence of tissue-specific isozymes of phosphofructokinase (33). A low peak exercise heart rate in PFKD relates to potential risks of extreme exertion, including rhabdomyolysis, myoglobinuria, and possible renal failure, which largely preclude exhorting patients with muscle glycolytic defects to fully maximal effort under most exercise conditions. 00 2max for the PFKD patients can be estimated by extrapolation from their slope of linear regression of heart rate (beats/min) on 0, uptake (Vmin), which averaged 131. With a mean heart rate in maximal
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rate equivalent to -50% of VOzmax (10). In contrast to PFKD, patients with a selective impairment in longchain fatty acid oxidation due to CPTD and normal access to muscle glycogen and blood glucose as oxidative fuels had virtually normal peak work rate, 0, uptake, and arteriovenous O2 difference. These findings are consistent with evidence that access to carbohydrate fuel sources is required for normal 0, extraction by working muscle and normal expression of maximal aerobic power (15) and with the hypothesis that reduced availability of oxidizable substrate in the form of muscle glycogen and blood glucose is a major reason for the exercise intolerance characteristic of PFKD. The very low peak O2 uptake, markedly attenuated rise in arteriovenous 0, difference, and essentially norma1 peak cardiac output in PFKD patients are quantitatively similar to values reported for patients with McArdle’s disease (X), who lack access to muscle glycogen but not blood glucose as oxidizable substrates. This finding implies that lack of access to muscle glycogen per se, is the specific disturbance in fuel availability
0
. FIG. 2. Slopes of linear regressions of cardiac output (&) (A) and heart rate (HR) (B) on O2 uptake (Vo,) in patients with muscle PFKD (n = ‘7) or CPTD (8 = 5) and in healthy subjects (HS, n = 6). Values are means * SE. *Significantly steeper (P < 0.001) slopes for PFKD patients than for CPTD patients or HS.
exercise assumed to be similar to that of the agematched healthy subjects, i.e., 186 beats/min, mean vo 2max for the seven PFKD patients is estimated to be -240 ml/min higher than their mean measured peak 0, uptake of 0.83 l/min. With correction for body weight, the estimated value for voZmax in PFKD (18 ml. min-l . kg-‘) would be 50% that of the healthy subjects (36 ml 4min-l kg-l). In contrast to the typical approximately threefold increase (from 5.3 to 16.4 ml/dl) of arteriovenous 0, difference from rest to maximal exercise for the healthy sedentary controls, arteriovenous 0, difference only rose -60% from rest (4.5 ml/dl) to peak exercise (7.1 ml/dl) in PFKD. Thus the subnormal peak O2 uptake of the PFKD patients was due primarily to markedly attenuated peak arteriovenous 0, difference reflecting a subnormal capacity for muscle 0, extraction. in PFKD of -50% normal corresponds closely to the percentage of i702,,, achievable by ultramarathon runners after depletion of muscle glycogen related to several hours of running (6) and reinforces the notion that the virtually exclusive use of lipid as oxidizable substrate normally can sustain a metabolic
PFKD Patlents 0 SL l SG q RA
= OR
l
n
0 a 0
cl
l q
l
0
a
n
A~%nax
Lactate
Prolonged
GIUCOW
3. Individual values for slopes of linear regressions of cardiac output (&) (A) and heart rate (HR) (B) on 0, uptake (oo,> in patients with muscle PFKD (n = 4) under control conditions, during lactate infusion, after fasting followed by prolonged exercise, and during glucose infusion. FIG.
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0 8
0 0 0
n El
Control
Lactate
Prolonged
Glucose
PFKD Patients 0 l 0 m
5
’
I
Control
I
Lactate
I
Prolonged
SL SG RA DR
I
Glucose
FIG, 4. Individual peak exercise values for work rate (A), O2 uptake (B), and arteriovenous 0, difference (C) in patients with muscle PFKD (n = 4) under control conditions, during lactate infusion, after fasting followed by prolonged exercise, and during glucose infusion.
primarily responsible for the impaired oxidative metabolism and associated exercise intolerance in PFKD. Supporting this conclusion are findings that -I) muscle glucose utilization normally accounts for only a low perqentage of total ATP production during exercise at vo 2max in healthy subjects (19) and Z) peak 0, uptake and arteriovenous 0, difference increased but remained abnormally low after glucose infusion in McArdle’s disease patients (15). Thus unavailability of glycogen to fuel oxidative metabolism normally makes phosphofructokinase-deficient muscle heavily dependent on oxidation of lipid fuels. Recent findings in healthy subjects are consistent with the view that the capacity of the systemic circulation for 0, delivery normally limits muscle oxidative
TABLE
2. Peak exercise data for PFKD Work
Control Lactate Post-pro1
W
l/min
16t,3
0.7O-tO.07 1.04+0.10 0.84t0.03 0.63+0.05
6.1t0.2 8.1*0.5 7.7kO.6 5.520.2
are means
systemic arteriovenous plus
prolonged
Cardiac a-v02 Diff, ml/d1
36+6 24t2 13+2
Glucose Values
qo,,
Rate,
exercise.
_t
patients
SE for 4 patients. Qo,, O2 difference; post-prol,
output, l/min
Heart Rate, beats/min
11.64t0.79 12.80&0.83 11.50t0.64 11.24+0.58
155al 159+3 144_t6 139&Z
O2 uptake; a-v& Diff, exercise after fasting
metabolism in large muscle exercise (34). In contrast, although we are unaware of measurements of muscle blood flow in PFKD, the normal peak cardiac output but low arteriovenous 0, difference in PFKD and the exaggerated limb blood flow in relation to work rate or 0, uptake in McArdle’s disease (24,30) support the conclusion that, in PFKD, muscle oxidative metabolism normally is not limited by 0, delivery. Results of interventions to increase availability of oxidizable substrate instead imply that rates of delivery and/or extraction of blood-borne oxidizable substrates normally are involved in limiting muscle oxidative metabolism in PFKD. These interventions consisted of providing substrates that bypass the metabolic defect at PFKD: 1) lactate, which serves as a source of pyruvate, the substrate required for maximal oxidative metabolism (lo), and 2) FFA. In PFKD, increasing availability of lactate via intravenous infusion increased peak exercise work rate more than twofold and peak O2 uptake and arteriovenous O2 difference by 48 and 3376, respectively. Experimental support for enhancement of exercise performance by lactate oxidation derives from findings that contraction of isolated muscle treated with the glycolytic inhibitor iodoacetate persisted considerably longer in the presence of 0, and lactate than in the presence of 0, alone (29). Findings in healthy human subjects are compatible with an important role for oxidation by working muscle of lactate infused or produced during exercise (2).
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In comparison with control conditions, the intervension of working muscle and enhances delivery of oxidiztion involving overnight fasting and prolonged exercise able substrate when substrate availability limits muscle increased plasma FFA almost twofold and peak exercise 0, extraction. Mechanisms for the exaggerated cardiac work rate, 0, uptake, and arteriovenous 0, difference an output slope likely include increased activation of medulaverage of 53, 20, and 260/c, respectively. Delivery of lary cardiovascular centers by impulses originating in FFA is a function of blood flow to active muscle and I) higher motor control areas in association with volunplasma FFA concentration. Because peak cardiac outtary motor effort, i.e., “central command,” and 2) thinly put after fasting and prolonged exercise was very simimyelinated and unmyelinated group III and IV skeletal lar to that under control conditions, the increased muscle afferents sensitive to stimuli related to muscle plasma FFA, peak 0, uptake, and arteriovenous 0, difenergy metabolism (37). The augmented cardiac output ference after fasting plus prolonged exercise implies response of the McArdle’s disease patients studied by that muscle oxidative metabolism in PFKD normally is Braakhekke et al. (la) could be interpreted to relate to limited in part by the rate of FFA delivery related to the an increased central command associated with muscle rate of FFA mobilization from adipose tissue. However, fatigue; however, a normal cardiac output-O, uptake repeak 0, uptake was not fully normalized by fasting plus lationship persists in healthy subjects during severe faprolonged exercise, and it is likely that other factors, tiguing effort (36). Normal cardiac output slopes in pasuch as the rate of extraction of plasma FFA by active tients with weakness due to muscular dystrophy (14) muscle, intramuscular triglyceride lipolysis, and the imply that an increased voluntary motor effort assorate of mitochondrial oxidation of FFA, limit the con- ciated with weakness of rested muscle that is present tribution of lipid substrates to oxidative metabolism in infrequently in PFKD (33) is not responsible for the exPFKD. aggerated cardiac output slope in PFKD. It has been In PFKD, although resting cardiac output was norargued (22) that steeper than normal cardiac output mal, there was an exaggerated slope of increase in car- slopes in McArdle’s disease primarily relate to augdiac output (l/min) with respect to 0, uptake (Vmin) mented activation of the muscle afferents with respect from rest to exercise. The normal 0, content of arterial to work or metabolic rate by an error signal originating blood is ~200 ml/l. Thus to increase 0, transport by 1 in active muscle associated with an exaggerated decline liter, cardiac output must increase by -5 liters. In in the muscle phosphorylation potential, [ATP]/ healthy human subjects, the slope of increase of cardiac [ADP][PJ, which is a quantitative expression of the caoutput on 0, uptake ranges from 4.6 to 6.3 with minor respiration and and inconsistent differences with respect to age, sex, pacity or potential for mitochondrial oxidative phosphorylation (4). However, inorganic body weight, and level of physical conditioning (cf. 9, 11), reflecting a normal, -1:l coupling of systemic O2 phosphate fails to rise normally in active phosphofructokinase-deficient muscle (8), and recent findings (1) transport and utilization (26). In contrast, a cardiac outsuggest that a subnormal [ATP]/[ADP] or simply an exput slope >11 in PFKD indicates a gross mismatch beaggerated accumulation of [ADP] may be a metabolic tween 0, transport and utilization specific to exercise. error signal common to phosphofructokinaseand phosNormal cardiac output slopes in patients with CPTD phorylase-deficient muscle. support the view that an exaggerated 0, transport reThe precise physiological and biochemical factors sponse to exercise in PFKD is not a general consequence likely to link subnormal muscle [ATP]/[ADP] or exagof abnormal muscle energy metabolism but relates gerated muscle [ADP] with augmented activation of closely to the virtually complete unavailability of oxidagroup III and IV muscle afferents are poorly undertive substrate in the form of glycogen, the primary intramuscular fuel. Consistent with this conclusion is the ex- stood. Nevertheless, evidence supporting reduced muscle ADP accumulation (22) in association with improved aggerated cardiac output slope of patients with vir0, extraction and normalization of cardiac output slope tually absent glycogenolysis due to McArdle’s disease during interventions to increase availability of oxidiz(la, 14, 23) and the essentially normal cardiac output able substrate in both PFKD and McArdle’s disease imslope and more normal peak 0, uptake in patients with between muscle oxidative glycogen-debranching enzyme deficiency (17,25), whose plies a close relationship phosphorylation and regulation of 0, transport. Experimuscles can oxidize a limited number of glucosyl units mental support for involvement of the muscle afferents from the outer branches of the glycogen molecule derives from findings linking reflex increases in cardiac through the normal action of phosphorylase (3). Partial in anesthenormalization of the exaggerated cardiac output slope output to muscle oxidative phosphorylation impaired muscle in PFKD during interventions to increase availability of tized animals (27). In experimentally oxidative phosphorylation and 0, extraction, blood flow alternative blood-borne oxidizable substrates, either lactate or FFA, supports this line of reasoning. In con- and cardiac output are exaggerated with respect to mettrast, no such normalization of cardiac output slope re- abolic rate (28,31), and there is a close inverse relationsulted from infusion of glucose, a substrate that cannot ship between blood flow and the ratio of [ATP] to its hydrolysis products (31). Recent findings of an exaggerbe oxidized by PFK-deficient muscle. Increases in peak 0, extraction accompanying parated 0, transport relative to metabolic rate in patients with defective muscle oxidative metabolism involving tially normalized cardiac output slopes in connection the mitochondrial respiratory chain (16) and citric acid with lactate infusion or fasting plus prolonged exercise in PFKD are compatible with the hypothesis that an cycle (13) are consistent with the hypothesis that norexaggerated cardiac output response augments perfumal oxidative phosphorylation in active muscle is cruDownloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (128.059.222.107) on January 16, 2019.
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cial for the normal coupling of 0, delivery zation in exercising humans.
IN HUMAN
and 0, utili-
The technical assistance of Karen Aayad, Marguerite Gunder, Paul Gustafson, Julius Lamar, and Willie E. Moore, Jr,, is gratefully acknowledged. We thank Dr. Gunnar Blomqvist for support and Dr. Salvatore DiMauro, Department of Neurology, Columbia University College of Physicians and Surgeons, for patient referrals. This research was supported by National Institutes of Health Grants HL-06296 and MOl-RR-00633, the Department of Veterans Affairs, the Muscular Dystrophy Association, and the Harry S. Moss Heart Center. S. F. Lewis is the recipient of Research Career Development Award HL-01581. Address for reprint requests: S. F. Lewis, Dept. of Health Sciences, Boston University, 635 Commonwealth Ave., Boston, MA 02215. Received 23 April 1990; accepted in final form 22 August 1990. REFERENCES
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Design
(2nd
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