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Published ahead of print on September 18, 2003, doi:10.1164/rccm.200303-363OC
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American Journal of Respiratory and Critical Care Medicine Vol 168. pp. 1476-1480, (2003)
© 2003 American Thoracic Society

Muscle Function and Resting Energy Expenditure in Female Athletes with Cystic Fibrosis

Hiran C. Selvadurai, Jane Allen, Toos Sachinwalla, James Macauley, Cameron J. Blimkie and Peter P. Van Asperen

Division of Respiratory Medicine, Hospital for Sick Children, Toronto, and Department of Kinesiology, McMaster University, Hamilton, Ontario, Canada; James Fairfax Institute for Nutrition, and Department of Respiratory Medicine, Childrens Hospital at Westmead, Westmead; and Rayscan Radiology, Liverpool, Sydney, Australia

Correspondence and requests for reprints should be addressed to H.C. Selvadurai, M.D., Department of Respiratory Medicine, Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8 Canada. E-mail: Hiran.Selvadurai{at}sickkids.ca


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The pathophysiology of impaired exercise tolerance in patients with cystic fibrosis (CF) is not completely understood. The objective of this study was to compare exercise ability (at clinical and cellular levels) and resting energy expenditure in female athletes with CF compared with matched control subjects. Sixteen subjects and matched control subjects participated in the study. The girls with CF not only had a significantly greater resting energy expenditure (7.6% higher; p < 0.05), their habitual daily activity was also significantly greater than that of control subjects (15% greater; p < 0.01). Peak aerobic capacity was similar in both groups. However, peak anaerobic power was 20% less (p < 0.05) in girls with CF. The 31P magnetic resonance spectroscopy studies demonstrated that there were no differences between the groups at rest, but at 25% total work output the girls with CF were less acidotic (CF, pH 6.99 [0.06]; control subjects, 6.90 [0.05]) and had a significantly lower inorganic phosphorus-to-phosphocreatine ratio (CF, 0.34 [0.07]; control subjects, 0.41 [0.08]). These differences continued to increase to maximal exercise. This study demonstrates that in spite of normal lung function and good nutritional status, females athletes with CF still had significant deficiencies in some measures of fitness and muscle metabolism compared with healthy athletes.

Key Words: exercise tolerance • aerobic capacity • anaerobic power

Life expectancy among patients with cystic fibrosis (CF) has improved dramatically (1, 2). Nutritional status, pulmonary function, and airway microbiology have all been shown to be independent predictors of survival (3).

The pathophysiology of reduced exercise tolerance in patients with cystic fibrosis is, however, not completely understood. As aerobic capacity is an important predictor of survival (3), the fact that girls with CF have a lower peak aerobic capacity than boys with CF of the same age (4) may be of relevance. Moreover, compared with reference values obtained in healthy girls, girls with moderate to severe CF-related lung disease have a significantly lower peak aerobic capacity (4). This finding has been attributed to reduced daily physical activity levels and nutritional status in girls with CF (4). If this were the complete answer, one would expect that well-nourished girls with mild CF disease without exercise limitation should have similar peak aerobic capacity and activity levels as healthy girls of the same age. Although intrinsic abnormalities in the skeletal muscle cells of patients with CF have been identified, the clinical impact of these abnormalities is unclear. Abnormalities have been demonstrated in the mitochondria of fibroblasts and leukocytes and include increased calcium concentration, lower nicotinamide adenosine dehydrogenase activity (respiratory chain enzyme complex) (5), and a higher pH optimum of nicotinamide adenosine dehydrogenase (6). Moser and colleagues have suggested that there is a muscle-related abnormality in oxygen metabolism in patients with CF (7).

The aim of this study was to compare exercise capacity (at clinical and cellular levels) and resting energy expenditure in female athletes with mild CF with matched healthy girls participating in the same sport.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
Included were girls with CF, 14 years of age or older, with "mild" CF disease, and participating in representative elite-level sport (either at regional or state level). "Mild CF" disease for the purposes of this study was defined by normal pulmonary function tests (forced expiratory volume in 1 second of greater than 80% predicted) and a Shwachman score (8) of greater than 90. The subjects were excluded if there was a history of pulmonary exacerbation in the 3 months preceding the test. For the purpose of the study, a pulmonary exacerbation was defined as increased cough and purulent sputum, in a child with malaise. The control population consisted of the female teammates of the girls with CF, matched for age and pubertal stage (9). Therefore, the control subjects participated in the same training activities and same sport as the subjects.

Sample Size
This study set out to study in our clinic the exercise ability of girls with CF who participated in high-level competitive sport. Using inorganic phosphate-to-phosphocreatine (Pi/PCr) ratio values representative of patients with chronic respiratory failure (10), we calculated that, if we recruited all 16 eligible subjects in our clinic, we would detect a 0.5 standard deviation difference in Pi/PCr ratio with a significance of 0.05% and a power of 90%. Payen and colleagues demonstrated that a 0.5 standard deviation difference in Pi/PCr ratio was clinically relevant (10).

Parameters of Assessment
Anthropometric.
Height was measured with a Harpenden stadiometer (Holtain, Crymych, UK) and body weight was measured by electronic floor scales (AND FW-150K; Tokyo, Japan). Skinfold thickness was measured with Harpenden skinfold calipers (British Indicators, St Albans, Hertfordshire, UK) at four sites (biceps, triceps, suprailiac, and subscapular). Body fat was then estimated from validated equations (11) and the fat-free mass was then calculated. The muscle plus bone cross-sectional area was calculated at midthigh during magnetic resonance imaging.

As per routine, all the patients in our CF clinic have genotyping performed at diagnosis.

Pulmonary function tests.
Complete pulmonary function tests including body plethysmography were performed with a spirometer (Sensormedics 2000; Sensormedics, Yorba Linda, CA). The primary parameters of assessment were forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and residual volume/total lung capacity (RV/TLC). Values presented by Weng and Levison (12) were used as the reference range.

Resting energy expenditure.
Resting energy expenditure was measured in the morning (8:00 A.M.–9:30 A.M.) by using a validated purpose-built ventilated hood indirect calorimeter (13, 14). Resting energy expenditure was measured over a 20-minute interval. All subjects fasted overnight and were asked to avoid any medications (specifically ß2-agonist bronchodilators) for 12 hours before testing. Validated equations were used to calculate energy equivalency from oxygen consumption and carbon dioxide production and estimated urinary nitrogen excretion reference (15, 16).

Exercise testing.
Peak aerobic capacity was assessed by a modified Bruce protocol (17) on an electronic treadmill (Cardiovit 100; Schiller, Baar, Switzerland). Breath-by-breath gas analysis was used to determine peak oxygen uptake (VO2), exercise ventilation (VE), and respiratory quotient (RQ). The peak aerobic capacity was assessed twice in each subject, with a 2-hour rest between each test. The anaerobic threshold was calculated by the method described by Beaver and colleagues (18). Maximum voluntary ventilation was measured directly by the sprint method (MVVSprint) as outlined by the American Thoracic Society (19). The breathing reserve, which is the difference between maximum voluntary ventilation and maximum exercise ventilation (20), was calculated. In addition, the subjects were requested to estimate their level of exertion on the basis of Borg's rating of perceived exertion score (21).

Nondominant leg strength was assessed with a Cybex dynamometer (Lumex, Ronkonkoma, NY). The muscles tested were the quadriceps femoris and the hamstrings. The best of three repetitions was recorded as the strength of the tested muscle group. The strength tests were performed on the same day as the exercise tests. Peak anaerobic power, mean power, and fatigue index were measured using the Wingate test (22) on an electronically braked cycle ergometer (Lode ergometer; Pro Med, Brampton, Ontario, Canada). Peak power and mean power were corrected for lean body mass for both groups of girls.

31P magnetic resonance spectroscopy.
Using their nondominant leg, each subject exerted maximal force for 2 seconds against a purpose-designed pressure-calibrated balloon followed by a 1-second rest period while lying prone in the magnetic resonance spectroscope (1.5-T nuclear magnetic resonance spectrometer; FEI, Hillsboro, OR). The nondominant leg was used for testing. The resting position of the flexed knee was 30 degrees from the horizontal (using a goniometer) while the subject lay prone in the magnetic resonance spectroscope. The leg was secured to the magnetic resonance spectroscope table 10 cm proximal from the medial femoral condyle. The exercise was repeated until exhaustion. The vastus medialis, vastus lateralis, vastus intermedialis, and rectus femoris muscles were exerted in this action. The force output exerted on the balloon was measured with a calibrated pressure transducer (Vacumed, Ventura, CA) and total work (cumulative force output) was calculated for the complete exercise protocol in the spectroscope. A computerized audiovisual metronome, designed specifically for the study, guided the subject through each phase of the exercise. Measurements of inorganic phosphorus (Pi), phosphocreatine (PCr), and intracellular pH were taken from the vastus lateralis muscle of the nondominant leg.

Habitual activity.
Each subject was asked to complete a 7-day activity diary (23) to assess habitual activity levels. These diaries had previously been validated for energy expenditure, using doubly labeled water (23). In addition, on the days on which the 7-day activity diary was being completed, the subjects were asked to wear a validated activity accelerometer (24) (WAM 7164; Computer Science and Applications, Shalimar, FL).

The study was approved by the ethics committee of the Royal Alexandra Hospital for Children and written consent was obtained from all participants and their parents when applicable.

Statistical Analysis
The group mean and standard error of the mean (SEM) were calculated for each parameter. The z scores were calculated for each subject's height and weight, using data from the National Center for Health Statistics (25). The lean body mass calculated on the basis of skinfold thickness was used to express peak aerobic capacity. Duncan's post hoc test of analysis of variance was used to assess differences between the groups for each of the key outcome variables. The SPSS-PC+ package (version 5.0; SPSS, Chicago, IL) was used for statistical analysis.

A curve utilizing nonlinear least-squares analysis, based on mixed Lorentzian and Gaussian line shapes, was used to calculate the areas under Pi, PCr, and ß-ATP peaks. This method has previously been described by Zanconato and colleagues (26). The Pi/PCR and PCr/ß-ATP ratios were then determined. Measurements were compared at rest, and at 25, 50, and 75% of maximal work output, and when maximal work output was reached. To compare the results from the magnetic resonance spectroscopy, two-tailed paired Student t-tests were used to compare mean differences between the group with CF and healthy control subjects. Values above the 95% confidence interval were considered statistically significant (p < 0.05).


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Sixteen girls with CF and their training partners took part in the study. All the subjects played elite-level representative sports and each girl with CF was paired with her training partner. The training partners were healthy and had no history of any respiratory complaints. The sports each pair of subjects participated in were netball (n = 5), basketball (n = 2), swimming (n = 4), hockey (n = 2), gymnastics (n = 2), and water polo (n = 1). All the girls with CF were treated with regular inhaled tobramycin. None of the girls with CF or control subjects were treated with inhaled corticosteroids.

The girls with CF had mild disease with a mean Shwachman score of 92.0 (SD, 7.0), and a mean forced expiratory volume in 1 second of 96% predicted (SD, 9) and were all pancreatic insufficient, requiring daily pancreatic enzyme replacement. The mean age and pubertal stage of the girls with CF participating in the study was 15.0 years (range, 13.2–17.3 years) and Tanner stage (27) breast 4.3 (SD, 0.6) and pubic hair 4.1 (SD, 0.4), respectively. This was not significantly different from the control subjects' mean age and pubertal stage of 14.9 years (range, 13.4–17.5) and Tanner stage (24) breast 4.4 (SD, 0.7) and pubic hair 4.2 (SD, 0.5), respectively. The demographic details of the study population are demonstrated in Table 1 . There were no significant differences between the girls with CF and control subjects in terms of anthropometric details. Of note, the midthigh muscle volume was not significantly different between the two groups (CF, 47.4 [3.2] cm2; control subjects, 48.1 [3.8] cm2).


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  		TABLE 1. Demographic details of study population

 
The genotype of the girls with CF consisted of those homozygous for {Delta}F508 mutation (n = 11), {Delta}F508/G542 (n = 2), {Delta}F508/R553X (n = 1), {Delta}F508/W1282X (n = 1), {Delta}F 508/R347H (n = 1). All the subjects were pancreatic insufficient, requiring pancreatic enzyme replacements with meals.

A comparison of the results for the girls with CF and control subjects is presented in Table 2 . The resting energy expenditure was 7.6% (p < 0.05) higher among the girls with CF. The girls with CF were also significantly more active both in terms of the activity diary (18.7%, p < 0.01), as well as the activity counts obtained from the accelerometer (15.0%, p < 0.01). The peak aerobic capacity in girls with CF was similar to that of their training partners. Both groups of study subjects exercised to exhaustion as demonstrated by the respiratory quotients being greater than 1.10. The anaerobic threshold occurred at about 59% of peak aerobic capacity for the both the girls with CF and the control subjects. The breathing reserve and Borg's rating of perceived exertion were not significantly different between the two groups.


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  		TABLE 2. Aerobic capacity, anaerobic power, and resting energy expenditure in female athletes with cystic fibrosis and control subject training partners

 
Girls with CF were significantly weaker when strength was measured using the Cybex dynamometer (p < 0.05). Similarly, the peak and mean anaerobic power of girls with CF was significantly lower compared with healthy control subjects (p < 0.05). The fatigue index (rate of decline of power) was significantly greater among girls with CF (p < 0.05).

The mean total work output generated by girls with CF, using this exercise protocol, was 170 J (SD, 35) whereas the healthy control subjects produced 246 J (SD, 41). This difference in total work output was statistically significant. There were, however, no significant differences between the two groups in the Borg's score at the termination of the 31P magnetic resonance spectroscopy test (CF, 9.5 [SE 0.8]; control subjects, 9.4 [SE 0.7]). The results of the 31P magnetic resonance spectroscopy study are presented in Table 3 . There were no significant differences in intracellular pH between the two groups at rest. However, girls with CF had a significantly higher pH at all work outputs greater than 25%. This is demonstrated graphically in Figure 1 . When comparison was made of the muscle pH between girls with CF after maximal work output was reached and control subjects after the same work output was achieved, (therefore, submaximal for control subjects) significant differences were demonstrated (pH 6.96 SE 0.06 and 6.86 SE 0.05, respectively; p < 0.05).


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  		TABLE 3. Results of 31p magnetic resonance spectroscopy study of female athletes with cystic fibrosis and control subject training partners

 


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  		Figure 1. Comparison of intracellular pH in girls with mild CF (closed columns) and healthy matched control subjects (open columns) at maximal work output. Error bars represent ± 1 SEM.

 
The Pi/PCr ratio was similar at rest in girls with CF and control subjects. However, at 25, 50, 75, and 100% work output, girls with CF had a significantly lower ratio than control subjects (Table 3). This is demonstrated graphically in Figure 2 . When comparison was made of the Pi/PCr ratio between girls with CF after maximal work output was reached and the matched control subjects after the same work output was achieved, significant differences were demonstrated (0.54 [SE, 0.08] in girls with CF versus 0.43 [SE, 0.06] in control subjects, p < 0.05).



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  		Figure 2. Comparison of inorganic phosphate-to-phosphocreatine ratio in girls with mild CF (closed columns) and healthy matched control subjects (open columns) at maximal work output. Error bars represent ± 1 SEM.

 
There were no significant differences in the phosphocreatine/ß-ATP ratio at rest between girls with CF and control subjects (Table 3). However, significant differences were noted at 25, 50, 75, and 100% total work output. When comparison was made of the phosphocreatine/ß-ATP ratio between girls with CF after maximal work output was reached and control subjects after the same work output was achieved, significant differences were demonstrated (1.90 [SE, 0.26] versus 2.07 [SE, 0.28], respectively; p < 0.05).

The mean recovery rate after the 3 minutes after exercise, measured in terms of the inorganic phosphate-to-phosphocreatine ratio, was 0.12/min for girls with CF and 0.24/min for healthy control subjects. This difference was statistically significant (p < 0.01).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study demonstrates that female athletes with mild CF have significantly lower anaerobic power and leg strength than control subjects. Resting energy expenditure and daily activity levels were significantly higher in the female athletes with CF than in control subjects. This study also provides support for intrinsic metabolic defects in skeletal muscles of patients with CF.

Neither group of subjects had significant respiratory limitation at the termination of the study. The girls with CF also reached their anaerobic threshold at a stage of the exercise test equivalent to that of healthy control subjects (about 60% of peak aerobic capacity). This suggests that muscle conditioning was similar in the girls with CF and control subjects.

The muscle strength and peak power of girls with CF was less than for control subjects. The peak power represents the energy-generating capacity of the high-energy phosphates while mean power represents the glycolytic capacity (28). The fatigue index reflects substrate acquisition and utilization for ATP production. The fatigue index in girls with CF was greater than in control subjects. This suggests that girls with CF were unable to rapidly acquire energy from substrates and therefore fatigued faster than control subjects.

Sedentary lifestyles may account for the reduced exercise tolerance in children with more severe CF disease (29). This is unlikely to be the explanation for these findings in our study as the girls with CF were more active than control subjects, as measured by diaries and accelerometers. Previous studies have demonstrated reduced exercise tolerance in patients with CF and concluded that inadequate nutrition together with respiratory limitation were the cause of this (30, 31). In our study, the nutritional status and lung function of the control subjects and girls with CF were normal. In addition, the muscle plus bone cross-sectional area was similar in both groups and therefore one cannot attribute our findings to diminished muscle volume. Like Moser and colleagues (7), we found that the total work per muscle size was lower in subjects with CF than in control subjects. Unlike patients with chronic obstructive pulmonary disease (32), our study suggests there is a preponderance of slow twitch fibers in our girls with CF. This is because peak aerobic capacity was similar in both study groups but peak power was significantly less in the CF group. Clearly, as our study group did not have any respiratory limitation at maximal exercise, it is not representative of all patients with CF.

The 31P magnetic resonance spectroscopy results demonstrated that girls with CF had significant differences in intracellular pH, inorganic phosphate/phosphocreatine ratio, and phosphocreatine/ß-ATP ratio during high-intensity exercise when compared with control subjects. These differences became statistically significant as the total work output increased. The demonstrated differences can be attributed to the fact that the girls with CF did less total work than control subjects in the magnetic resonance spectroscope. However, a comparison between the groups when the same amount of work was completed still demonstrated significant differences in all variables. Although aerobic and anaerobic mechanisms for ATP production run concurrently, the anaerobic mechanism is predominant at the onset of exercise and as the work output increases. As muscle work output increases, adenosine diphosphate (ADP) and inorganic phosphate (Pi) are released from the breakdown of ATP and phosphocreatine (PCr). The ratio of Pi to PCr is thus directly proportional to the rate of mitochondrial oxidative metabolism (33). As the rate of ATP hydrolysis approaches the maximal rate of tissue oxidative phosphorylation, anaerobic glycolysis, activated by ADP and Pi, becomes the principal metabolic mechanism for energy production. Glycolysis results in the accumulation of lactic acid and hydrogen. By measuring hydrogen, magnetic resonance spectroscopy is able to quantify intracellular acidosis. This study demonstrated that despite high-intensity exercise, girls with CF did not develop significant intracellular acidosis. This suggests that the rate of anaerobic glycolysis in girls with CF may be insufficient to meet the energy demands of the exercising muscle. The Pi/PCr ratio at maximal work output, which reflects mitochondrial oxidative metabolism, was significantly lower in girls with CF compared with healthy control subjects. The results provide support for Shapiro's hypothesis that that there is an intrinsic mitochondrial defect in the muscles of patients with cystic fibrosis (34). When the same quantity of work was performed, the Pi/PCr ratio was significantly higher in girls with CF compared with healthy control subjects. This suggests that mitochondrial oxidative metabolism in girls with CF is inefficient, requiring utilization of greater phosphocreatine stores to perform the same amount of work as the healthy control subjects. The ratio of PCr to ß-ATP is similarly consistent with a reduced maximal mitochondrial oxidative capacity as well as inefficient mitochondrial oxidative metabolism compared with control subjects.

Using the same techniques, De Meer and colleagues (35) demonstrated similar results in patients with CF. However, that study was performed in patients with poor nutritional status and severe CF disease, in whom peripheral muscle limitation is well described (31, 32). We believe ours is the first study to demonstrate deficiency in patients with CF and excellent nutritional and respiratory status.

The resting energy expenditure of the female athletes with CF was significantly greater than that of control subjects. These results are consistent with a study from our laboratory (36) and other laboratories (37, 38). As all the patients were clinically stable, the resting energy expenditure values were likely to be repeatable (12). All the subjects with CF were colonized with the microorganism Pseudomonas aeruginosa and this has been shown to increase metabolic demand (39) and may explain the higher resting energy expenditure. It does, however, seem implausible that colonization alone in the absence of symptoms could account for the greater resting energy expenditure (40).

We have previously demonstrated that the patients with milder cystic fibrosis transmembrane conductance regulator (CFTR) mutation classes (41) have better exercise tolerance (42). It may be that the CFTR, which is involved in transmembrane chloride transport and is expressed in skeletal muscles (43), may be affecting both oxidative and anaerobic metabolism. Ramjeesingh and colleagues (44) demonstrated the catalytic and chloride channel gating properties of the CFTR. Of importance to this study, the CFTR has ATPase activity, which results in depletion of energy stores such as phosphocreatine. The CFTR protein has been shown to cause ATP hydrolysis (45). This is a possible mechanism for the inefficient oxidative and anaerobic metabolism demonstrated in this study.

In conclusion, we have demonstrated that female athletes with mild CF still had measurable impairments in exercise tolerance, muscle strength, and power. In addition, the resting energy expenditure and daily activity levels were significantly higher in elite female athletes with CF than their training partners. This study has also demonstrated that female athletes with CF had dysfunctional muscle metabolism during high-intensity exercise. It is not known whether the same occurs in male patients with CF.


   Acknowledgments
 
H.C.S. has no declared conflict of interest; J.A. has no declared conflict of interest; T.S. has no declared conflict of interest; J.M. has no declared conflict of interest; C.J.B. has no declared conflict of interest; P.P.V.A. has no declared conflict of interest.

Received in original form May 12, 2003; accepted in final form September 16, 2003


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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
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