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European Journal of Heart Failure 2000 2(1):53-63; doi:10.1016/S1388-9842(00)00058-1
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© 2000 European Society of Cardiology

The effect of physical training on skeletal muscle in patients with chronic heart failure

K. Kiilavuoria,*, H. Näveria, T. Salmib and M. Härkönenc

a Department of Medicine, Division of Cardiology, Helsinki University Central Hospital Haartmaninkatu 4, 00290 Helsinki, Finland
b Department of Clinical Neurophysiology, Helsinki University Central Hospital Haartmaninkatu 4, 00290 Helsinki, Finland
c Department of Clinical Chemistry, Helsinki University Central Hospital Haartmaninkatu 4, 00290 Helsinki, Finland

* Corresponding author. Department of Medicine, Jorvi Hospital, Turuntie 150, 02770 Espoo, Finland. Tel.: +358-9-861-5324; fax +358-9-861-5906.


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Background: The improvement of exercise capacity in patients with chronic heart failure (CHF) by physical training has been connected with reversal of the abnormalities in muscle fiber distribution and with the reduced activity of the enzymes of oxidative metabolism in skeletal muscle. However, the change in fiber type distribution induced by training is controversial and in previous studies the activities of the rate-limiting enzymes of the metabolic pathways have not been measured.

Aims: To examine the effect of dynamic training on percentage distribution of muscle fibers, on activities of the rate-limiting enzymes of the metabolic pathways and on electrophysiology in skeletal muscle.

Methods: A total of 27 patients with stable CHF (NYHA class II–III) were randomized to a training (N=12) or a control (N=15) group. The training group exercised on a bicycle ergometer for 30 min three times a week for 3 months using a load corresponding to 50–60% of their peak oxygen consumption. This was followed by a 3-month training period at home according to personal instructions. The control group did not change its physical activities. We studied muscle histology and measured the activities of the rate-limiting enzymes of anaerobic glycolysis (phosphofructokinase, PFK), glycogenolysis (phosphorylase), citric acid cycle ({alpha}-ketoglurate dehydrogenase, KGDH) and fatty acid oxidation (carnitinepalmitoyl transferase I and II, CPT I and II) from biopsies of the vastus lateralis muscle at baseline and after 3 and 6 months. Muscle strength and strength endurance with surface EMG and macro EMG of the right knee extensors were also determined.

Results: Exercise capacity, particularly submaximal, improved in the training group. The activity of PFK rose significantly but that of the other enzymes did not when compared with the change in the controls. Training had no effect on the percentage distribution of slow-twitch and fast-twitch muscle fibers or on capillary density around these fibers in skeletal muscle. Maximum voluntary force, strength endurance and the function of motor units remained unaffected.

Conclusions: Dynamic training results in improved exercise endurance in CHF. In skeletal muscle, the capacity of anaerobic glycolysis is increased but that of the citric acid cycle and fatty acid oxidation is not. Furthermore, the improvement in exercise endurance seems to be independent of changes in the percentage distribution of muscle fibers, capillarity or electrophysiological factors.

Key Words: Chronic heart failure • Physical training • Skeletal muscle • Histology • Enzymes • Electrophysiology

Received April 7, 1999; Revised December 16, 1999; Accepted December 23, 1999


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Peripheral mechanisms have been proposed to be the cause of early muscle fatigue in patients with chronic heart failure (CHF). Early anaerobic metabolism and a fall in skeletal muscle pH due to rapid muscle lactate accumulation with depletion of the direct energy sources adenosinetriphosphate and phosphocreatine have been observed [1–3]. The reduction in vasodilatory capacity [4,5] and increase in resistance to blood flow [6] results in a reduction of blood flow to the working skeletal muscle [7,8]. Skeletal muscle biopsies have detected a reduction in the proportion of oxidative slow-twitch muscle fibers, an increase in the proportion of glycolytic fast-twitch fibers [9] and a reduction in enzyme activities involved in oxidative metabolism [3,10].

Physical training has been shown to improve aerobic capacity and metabolism in patients with CHF [11]. It has been reported to increase the volume density of mitochondria [12,13], induce a rise in the enzyme activities involved in aerobic metabolism and increase the proportion of slow-twitch fibers in skeletal muscle [14,15]. However, the enzymes of the citric acid cycle and fatty acid oxidation analyzed in these studies do not catalyze rate-limiting, non-equilibrium reactions and thus cannot reliably estimate the capacity of the associated metabolic pathway [16]. Furthermore, there is no evidence in healthy persons that fast-twitch (type II) muscle fibers can be converted to slow-twitch (type I) muscle fibers by means of physical training [17].

Earlier we have shown that physical training of moderate intensity markedly improves exercise endurance at submaximal work loads with a smaller change in peak oxygen consumption [18]. In the present study, using the same patient material, we hypothesized that an improvement in skeletal muscle metabolism contributes to this training effect without any change in the percentage distribution of slow-twitch and fast-twitch muscle fibers. Accordingly, we determined from samples of quadriceps femoris muscle the activities of the rate-limiting enzymes of the main metabolic pathways, i.e. anaerobic glycolysis, glycogenolysis, the citric acid cycle and fatty acid oxidation, the percentage distribution of the muscle fibers together with fiber size and capillary density at baseline after 3 and 6 months in the training and the control group. We also hypothesized that the effect of dynamic training is transmitted on muscle strength and strength endurance. The training effect on muscle electrophysiology, which has been little studied in CHF, was also evaluated.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusions
 References
 
2.1. Patients
The study group comprised 27 patients, who were randomized to a training (N=12) or a control group (N=15). The patients were under 65 years of age and had a CHF history longer than 6 months. The etiology of the CHF was dilated cardiomyopathy or ischemic heart disease. The diagnosis and the etiology were established by routine clinical examination, two-dimensional and M-mode echocardiography and right heart catheterization. The disease had been stable for more than 3 months in NYHA class II (N=15) or III (N=12). The left ventricular ejection fraction was <40% measured by echocardiography. All patients with an ischemic etiology had a history of myocardial infarction but had neither symptomatic angina nor electrocardiographic evidence of ischemia limiting exercise capacity. None had a pulmonary disease or diabetes. Cardiac medication was kept stable, if possible, but a change in the diuretic dose was allowed during the study. The patients gave an oral informed consent for this trial, which was approved by the local ethics committee. The investigation conformed with the principles outlined in the Declaration of Helsinki.

2.2. Training
Training was totally dynamic, no strength training was included. It comprised of a supervised period followed by a self-training period, both of 3 months duration. The supervised training was performed by ergometer cycling for 30 min three times a week. During the first 2–3 weeks the load corresponded to 50–60% of the peak oxygen consumption at the baseline. Later the load was adjusted according to the heart rate, which was maintained at the same level. The supervisor was a physician. The self-training was performed at home by walking, cycling, rowing and swimming according to personal instructions. No diary was kept during the latter period but the compliance was estimated by an interview. The control patients were advised not to change their previous physical activity during the 6 months.

2.3. Exercise testing
Both a graded maximal exercise test and an exercise test with constant submaximal work load were performed at baseline and after 3 and 6 months as described previously [18].

2.4. Skeletal muscle samples
The muscle biopsy was taken at baseline and after 3 and 6 months between 14.00 and 15.00 h on a non-exercise day. The subject lay in the supine position and a Bergström needle using suction was employed to sample the lateral portion of the quadriceps femoris muscle. After local anesthesia of the skin a small incision was made with a scalpel and the biopsy needle was advanced 3–4 cm into the muscle mid way between the greater trochanter and the knee. The subsequent biopsies at 3 and 6 months were taken 5 cm apart from the previous ones to avoid the earlier biopsied muscle area. The samples were frozen immediately in liquid nitrogen and stored at –70°C until analyzed.

2.4.1. Fiber distribution, size and capillary density
Serial 10-µm transverse sections were cut with a cryostat at –20°C and mounted on cover glasses. Muscle fiber types were identified by staining for myosin ATPase activity after preincubation at pH 4.35. The number of muscle fibers, of each type, was counted visually. The muscle fiber size was determined with a computerized digitizing program by drawing along the edges of the fibers. The capillaries were stained immunohistochemically (Vectastain Elite ABC kit, Vector Laboratories, Burlingame, CA, USA). The number of capillaries adjacent to each muscle fiber was counted visually from the microscope’s monitor screen.

2.4.2. Enzyme activities
For the determination of enzyme activities the muscle samples were homogenized in 10 volumes of 50 mmol/l Tris–HCl buffer, pH 7.4, containing 0.5 mmol/l dithiothreitol (DTT), 2 mmol/l MgCl2 and 1 mmol/l EDTA. Protein content of the water-diluted homogenates was measured according to Lowry et al. [19]. The kinetics of the reactions were followed in Transcon 102 FN fluoronephelometer (Elomit Ltd, Helsinki, Finland). All samples of each patient were analyzed simultaneously.

2.4.2.1. Phosphorylase (PHRL) and active phosphorylase (PHRLa)
The activity was measured by a modification of a method by Härkönen et al. [20,21]. The assay medium for total PHRL contained 50 mmol/l Imidazole-HCl buffer, pH 7.0, 0.5 mmol/l MgCl2, 20 mmol/l K2PO4, 0.1 mmol/l EDTA, 0.5 mmol/l DTT, 0.1 mmol/l NADP+, 5 mmol/l glycogen (as glycosyl units), 0.02% bovine serum albumin (BSA), 1 mmol/l 5-AMP, 600 mU/ml phosphoglucomutase and 280 mU/ml glucose-6-phosphate dehydrogenase. For PHRLa the assay medium did not contain 5-AMP. The increase of NADPH fluorescence was followed at +25°C. In calculations 5 µmol/l of glucose-6-phosphate was used as calibrator.

2.4.2.2. Phosphofructokinase (PFK)
Assay medium was principally the same as described by Lowry et al. [22] and contained 50 mmol/l Tris–HCl, pH 7.4, 1 mmol/l ATP, 2 mmol/l mgCl 0.02% BSA, 10 mmol/l K2HPO4, 1 mmol/l AMP, 1 mmol/l DTT, 10 µmol/l NADH, 50 U/ml triosephosphate isomerase, 90 mU/ml aldolase and 1 U/l glycerin-3-phosphate dehydrogenase. The reaction was initiated by adding 2 mmol/l of fructose-6-phosphate, and the disappearance of NADH was followed kinetically at +25°C for 1–2 min.

2.4.2.3. {alpha}-Ketoglutarate dehydrogenase (KGDH)
Assay medium contained 100 mmol/l Tris–HCl, pH 7.4, 2 mmol/l DTT, 1 mmol/l KCN, 0.4 mmol/l ADP, 1 mmol/l NAD+ and 0.5 mmol/l CoA. The reaction was initiated by adding 1 mmol/l of {alpha}-ketoglutarate. Formation of NADH was followed kinetically at +25°C for 2–3 min. In calculations 5 µmol/l of NADH in final concentration in the assay medium was used as calibrator.

2.4.2.4. Carnitine palmitoyltransferase I (CPT I)
The release of CoA in the reaction with palmitoyl-CoA and carnitine was used as an index of enzyme activity. The assay medium contained 100 mmol/l Tris–HCl buffer, pH 7.4, 80 mmol/l KCl, 1 mmol/l KCN, 1 mmol/l EDTA, 0.1% BSA, 1 mmol/l {alpha}-ketoglutarate, 0.5 mmol/l NAD+, 1 mmol/l carnitine and 50 mU/ml KGDH. The reaction was initiated by adding 50 µmol/l palmitoyl-CoA and followed kinetically at +25°C for 2–3 min. In calculations 5 µmol/l of NADH was used as calibrator.

2.4.2.5. Carnitine palmitoyltransferase II (CPT II)
Formation of carnitine in the reaction between palmitoyl–carnitine and CoA was used as an index of enzyme activity. The method of Deufel and Wieland [23] was used with the following modifications: Carnitine formed in the reaction was measured using carnitine acetyltransferase. CoA formed in this reaction from acetyl-CoA was measured in the medium containing 50 mmol/l Imidazole-HCl buffer, pH 6.7, 1 mmol/l MgCl2, 0.5 mmol/l EDTA, 0.5 mmol/l NAD+, 0.5 mmol/l {alpha}-ketoglutarate, 1 mmol/l DTT, 0.02% BSA and 0.1 mmol/l acetyl-CoA and 40 mU/ml of KGDH. Both 400 µl of this solution and 20 µl of CoA-containing medium were pipetted to Transcon microcuvettes, initial fluorescence was read and the reaction initiated by adding 20 mU of carnitine acetyltransferase. The reaction was completed in 5 min at +25°C, and formation of carnitine was calculated. Carnitine in concentration of 5 µmol/l was used as calibrator.

2.5. Muscle strength and electrophysiology
Two protocols involving the knee extensors were performed to assess muscle strength and endurance. The patients were seated in a special chair to standardize the limb position to 90° flexion of the knee and to immobilize the trunk. A force transducer was placed on the anterior edge of the lowest third of the tibia and the force was recorded with Kyowa dynamometer (Kyowa Electronic Instruments Co, Tokyo, Japan).

In the first protocol the patients were encouraged to perform two maximal 3-s voluntary contractions of the right quadriceps femoris separated by 1 min of rest. The better of the two was taken as the maximal voluntary contraction. The time in which 90% of that force was achieved was determined. In the second protocol, after 4 min rest, the patients maintained a maximal voluntary contraction for 40 s. The mean force and the slope of force reduction reflecting strength endurance were determined. The contraction force was monitored on-line during both protocols. A two-channel surface EMG was registered during the second protocol using electrode pairs at separation of 30 mm and situated parallel to vastus lateralis muscle fibers [24]. The EMG signals were amplified by Dantec EMG equipment (Dantec, Skovlunde, Denmark), sampled digitally and analyzed off-line to calculate the muscle fiber conduction velocity and velocity slope.

Macro-EMG amplitude and area were determined during slight voluntary contraction of the right quadriceps femoris muscle in the supine position [25].

These tests were performed for 21 patients (training=8 and, control=13) because the equipment was not in our use until the first six patients had entered the study.

2.6. Statistical analysis
The Mann–Whitney U-test was used to compare the groups at baseline. Repeated measures analysis of variance was used to test the changes between the groups during the study. When a significant change was detected Fisher’s protected least significant difference was used to isolate it. The level of significance was set at P<0.05. The data are given as mean ± S.E.M. unless otherwise stated.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusions
 References
 
3.1. Baseline characteristics
The baseline characteristics of the trained and control group are represented in Table 1. The groups did not differ from each other. One patient in the control group was hospitalized 1.5 months after the beginning of the study due to significant fluid retention. His data are not included in the analyses.


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  		Table 1 Clinical characteristics of the patients in the control and the training group at baselinea

 
3.2. Exercise capacity
Physical training significantly reduced the symptoms of heart failure and improved exercise capacity as we have reported previously [18]. In short, the New York Heart Association functional class improved from 2.4±0.1 at baseline to 1.9±0.2 after both 3- and 6-month observation periods in the training group (P<0.01 vs. controls). Exercise duration in the bicycle test with a constant submaximal work load almost doubled during the 3-month supervised training period and this level was preserved during the home-based training period (P<0.01 vs. controls). The peak oxygen consumption was 12% higher after training. This change was not significant within the group but significant compared with the change in the control group (P<0.05).

3.3. Fiber distribution, size and capillary density in skeletal muscle
The average number of muscle fibers in each biopsy sample was 195. Two patients from the control group were excluded from the analyses of muscle fiber distribution because of the small number of muscle fibers in the biopsy. On the basis of the quality of the histological sections and staining, 16 patients (training=7 and control=9) could be included in the analyses of capillary density and 18 patients (training=9 and control=9) in the analyses of fiber size.

Training did not change the percentage distribution of slow-twitch and fast-twitch muscle fibers, the mean size of all fibers, or the mean size of the two fiber types were compared with the control group (Table 2). The number of capillaries adjacent to slow-twitch muscle fibers was significantly higher than the number adjacent to fast-twitch muscle fibers in both groups, but the number of capillaries adjacent to each fiber remained unchanged around both slow-twitch and fast-twitch muscle fibers in both groups (Table 2).


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  		Table 2 The skeletal muscle fiber distribution percentage, mean fiber size and capillary density in the control and the training group during the studya

 
3.4. Enzyme activities in skeletal muscle
The enzyme activities could be determined in all 12 patients in the training group and in 13 patients in the controls. The activities of both PHRL and PHRLa remained unchanged in both groups (Fig. 1a,b). The activity of PFK increased significantly in the training group during the study period compared with the control group (P<0.05). After the supervised training the mean PFK activity was 52% higher than at baseline (Fig. 1c). Individually, nine patients in the training group had higher PFK activity at both 3 and 6 months compared with baseline. This was the case in one control patient. The activity of KGDH did not alter in either group (Fig. 1d). Training did not change the activity of CPT I compared with the control group, although the mean activity was 44% higher at 3 months and 64% higher at 6 months compared with baseline (Fig. 1e). In the control group the rise was 15 and 28%, respectively. At baseline, the activity of CPT I was lower in the training group than in the controls (P<0.05). The activity of CPT II remained unaltered in both groups (Fig. 1f).


Figure 1
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  		Fig. 1 Skeletal muscle enzyme activities in the control (open bars) and the training (grey bars) groups at baseline (0) and after 3 and 6 months. PHRL, phosphorylase; PHRLa, active phosphorylase; PFK, phophofructokinase; KGDH, {alpha}-ketoglutarate dehydrogenase; CPT, carnitinepalmitoyl transferase; and #, P<0.05 for difference in the changes from baseline between the groups. The data are given as mean±S.E.M.

 
3.5. Skeletal muscle strength and electrophysiology
The maximal voluntary force of the knee extension did not change nor was there a change in the rapidity with which the force was produced in either group (Fig. 2a,b). The mean force during the 40-s strength test was 653±51 N at baseline but 815±96 N at 6 months in the training group (Fig. 2c). This change was not significant compared with the control group. The slope of force reduction remained unchanged (Fig. 2d). There was no alteration in muscle fiber conduction velocity or in the change of the velocity during the 40-s strength test (Fig. 2e,f). The macro-EMG amplitude and macro-EMG area also remained unchanged (Fig. 2g,h).


Figure 2
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  		Fig. 2 Maximal voluntary force of right knee extensors (panel a) and the time required to achieve 90% of it (panel b) during 3-s maximal voluntary contraction. Mean force (panel c), rate of force reduction (panel d), muscle fiber conduction velocity (panel e) and change of the velocity (panel f) in the right knee extensors during 40 s maximal voluntary contraction. Macro-EMG amplitude (panel g) and area (panel h) of the right quadriceps femoris during light voluntary contraction. The open bars are for the control group and the grey bars for the training group. Measured at baseline (0) and after 3 and 6 months. The data are given as mean±S.E.M. (N, newton.)

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusions
 References
 
Our study shows that dynamic physical training of moderate intensity, which improves particularly the submaximal exercise endurance, increases the activity of PFK, the rate limiting enzyme of anaerobic glycolysis, in skeletal muscle. However, we did not find an increase in the activity of the CPT complex and KGDH, the rate limiting enzymes of fatty acid oxidation and the citric acid cycle, respectively, compared with the control group. This type of training of moderate intensity does not have an effect on maximal voluntary strength or strength endurance. It does not affect the size, the percentage distribution of slow-twitch and fast-twitch muscle fibers or the capillary density around these fibers in skeletal muscle. Neither does the improvement in exercise endurance seem to be associated with changes in skeletal muscle electrophysiological properties.

4.1. Skeletal muscle histology
Previous studies have shown marked changes in skeletal muscle histology in patients with CHF. Muscle atrophy is also present in patients with mild or moderate heart failure and even without documented weight loss [9,26]. The percentage of fast-twitch, type II or IIb fibers has been shown to be higher and accompanied by a reduction in the size of the fibers compared with healthy subjects [10,27]. A lower percentage of slow-twitch, type I fibers has also been reported in small studies [10,28,31].

According to our study physical training does not affect the percentage distribution of muscle fibers in skeletal muscle. Similar results have been published previously in studies where patients with CHF have participated in low intensity endurance training [12] or intensive strength training [29]. However, these and the present study have been small (11–18 patients in the training groups), which makes this conclusion uncertain. Interestingly, however, Hambrecht et al. [15] found a significant increase in the proportion of slow-twitch fibers as a result of a very intensive 6-month program of dynamic training with an even smaller number of patients. Our opinion is that a true change is open to question. This is emphasized by the coefficient of intra-individual variation of 5–8% for fiber composition in the vastus lateralis muscle in normals [30], though the variation in patients with CHF has not been reported. In different studies the proportion of slow-twitch muscle fibers has varied from 18 to 49% in these patients [10,12,15,31]. The survey is complicated by inclusion of very differing patients, heart failure of varying severity and etiology and by differing histological techniques [32]. In healthy persons even strenuous exercise does not cause a conversion of fast-twitch fibers into slow-twitch fibers but it does increase the size of the fibers [33,34]. However, it can be speculated that hypoperfusion with probable episodes of hypoxaemia and reperfusion together with the direct influence of neurohumoral factors on skeletal muscle can cause a true transformation of slow-twitch fibers to fast-twitch fibers in CHF patients, which could be reversed by training.

The mean size of either fiber type did not alter in our study. This is in contrast with earlier studies, which have demonstrated an increase in muscle fiber size after both strength and endurance training [12,29]. Our result may suggest that the training intensity was not high enough to induce any changes or that due to the small number of analyzable sections the possible changes could not be detected.

Capillary density around muscle fibers has been reported to be normal [9,28] or reduced [10] in patients with CHF. On the other hand, training has been shown to increase peak leg blood flow and peak reactive hyperemia in these patients [35,36]. In the present study there were no intergroup differences between the changes in capillary density. However, the contribution of capillary density to the training effect is difficult to evaluate on the basis of this study because the sections of only seven patients in the training group and of nine patients in the control group were analyzable. Previously, intensive one-legged strength and strength plus endurance training has been reported to increase the capillary per fiber ratio by 50%, however, the comparison with the change in the control leg was not reported [29]. In another study low intensity physical training, which improved peak VO2 resulted in a similar outcome to ours [12].

As a matter of fact, the pathophysiological importance of capillary density, assessed from skeletal muscle sections, is not known in CHF. Instead, it is evident that maldistribution of circulation within the working muscle is of major importance [4]. The significance of the latter factor has been shown in a recent study on a rat model of CHF [37]. According to this study the linear density of capillaries was increased but the percentage of capillaries continuously perfused by red blood cells was reduced and the red blood cell flux per unit tissue was markedly lower in CHF rats compared with the controls.

4.2. Skeletal muscle metabolism
To measure the maximum flux of a metabolic pathway, an indicator enzyme catalyzing a non-equilibrium reaction should be chosen [16]. Thus, we measured the activities of PHRL and PHRLa as indices of glycogenolysis, PFK as an index of anaerobic glycolysis, KGDH as an index of the citric acid cycle and CPT I and CPT II as indices of fatty acid oxidation. When the activity of enzymes catalyzing near-equilibrium reactions are measured (e.g. citrate synthase in the citric acid cycle and 3-hydroxyacyl-CoA dehydrogenase in fatty acid oxidation), the maximal activity of the enzyme may be an order of magnitude greater than the maximum flux through the pathway and cannot describe the maximal capacity of the pathway. KGDH is probably the only enzyme that can provide quantitative information on the aerobic capacity of a muscle [16]

We found a significant increase in the activity of PFK in the training group compared with the controls. The activity of PFK in the vastus lateralis muscle of patients with CHF has been found to be similar to or less than that in healthy subjects [3,10,38]. In the present study, the level of PFK activity at baseline was well below that of patients with moderate CHF and healthy controls in our previous study [3]. In healthy subjects, moderate endurance training has no effect on anaerobic glycolysis and glycogenolysis but heavy intensity training has been shown to enhance the activity of PFK [33]. In CHF the data about the effect on anaerobic glycolysis is very scanty. Training has been reported to have no effect on the activity of 3-phosphoglycerate kinase [29], but reduced activity of PFK has been shown to be increased after 5–6 weeks’ treatment with captopril in patients who were in the NYHA III functional class [38]. The latter result may reflect a direct beneficial effect on the circulation and metabolism of skeletal muscle but it could be mediated via increased activity, although the treatment period was rather short. We, therefore, suggest that, although our training intensity was moderate, it could have anaerobic periods, particularly in the beginning, during the supervised training. The partial reversal of the increase in PFK activity during the home-based training, which did not reach the same intensity, supports this view. These results may also reflect a faster response of the glycolytic pathway to exercise, particularly in patients with CHF.

In this study the activity of KGDH was markedly lower at baseline compared to that in the healthy persons of our previous study [3] reflecting a decreased maximal flux through the citric acid cycle in patients with CHF. Previously, the activity of citrate synthase and succinate dehydrogenase have been shown to be lower in patients with CHF [39,40]. However, in the present study we did not find a training-induced increase in the activity of KGDH. The explanation may be that the training stimulus was not sufficient, which did not cause a marked increase in peak oxygen consumption. In previous studies, volume density of mitochondria, which relates to improved aerobic metabolism in skeletal muscle, has been shown to increase in association with a significant increase in peak oxygen consumption [12,13].

The activity of 3-hydroxyacyl-CoA dehydrogenase, which is an enzyme of the β-oxidation cycle of fatty acids in the mitochondrial matrix, has been shown to be reduced in CHF [10,27,40]. Furthermore, the only study evaluating the activity of CPT complex, which translocates fatty acids into mitochondria, reported a decrease in the CPT II activity [3]. Instead, the present study could not demonstrate a difference between the changes in the activity of the CPT complex in the training and the control group. The increase in the level of CPT I activity in the training group suggests that this might be due to the low statistical power of the study resulting from the small number of patients and the variation of the enzyme activities. The more efficient utilization of fatty acids during exercise is suggested by the delayed increase of respiratory quotient at submaximal work loads, which we have reported previously from the same material [18]. Dynamic training has previously been reported to increase the activity of 3-hydroxyacyl-CoA dehydrogenase [29], but this enzyme does not reflect the maximal rate of fatty acid oxidation. Neither was the comparison of the change with that in the control leg reported.

4.3. Skeletal muscle strength and electrophysiology
In the present study dynamic training did not improve the maximal voluntary strength and the strength endurance of the knee extensors compared with the control group. Marked improvement has previously been achieved by training of local muscle groups [14,29,41]. This is a probable change, but none of the investigators reported the comparison between the changes in the training and the control group.

We could not use a superimposed electrical stimulus during the strength tests. Instead, we monitored on-line the contraction force and the similarity of the two maximal voluntary contractions suggests that they were maximal. Likewise, the shape of the 40-s force measurement without any fast fluctuations of the curve suggests that this contraction was also maximal. It has been reported earlier that, ensured by an electrical stimulus, patients with CHF can voluntarily produce maximal or nearly maximal force [42,43]. Instead, during fatiguing exercise it is probable that the recruitment of muscle fibers is dependent on whether the protocol is isokinetic or isometric. It has been shown that after the former, the patients are able to fully activate their knee extensors [44]. Instead, Minotti et al. [43] reported that, after a fatiguing isometric contraction of the foot dorsiflexors, neural drive appeared to be a limiting factor for force production. Importantly, however, the patients with CHF did not differ in this regard from normal healthy controls. The effect of the extra stimulus after sustained isometric contraction could be explained by recruitment of type II fibers after sustained contraction produced fully by type I fibers.

In this study changes in muscle or nerve electrophysiology were not found. This supports previous reports, which show that muscle fatigue in patients with CHF is not caused by impaired central motor drive nor by an abnormality of neuromuscular junction transmission [43,44].

4.4. Limitations
The small size of the two groups is the major limitation of our study. In particular, this is emphasized in parameters, the levels of which have wide variation like the activities of enzymes in skeletal muscle.


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
References
 
Our results suggest that improved energy metabolism in skeletal muscles plays a part, like in healthy people, in training-induced enhancement in exercise capacity in patients with CHF. That was shown by the increased activity of PFK, the rate-limiting enzyme of glycolysis. In spite of the improved exercise endurance the change in the capacity of citric acid cycle and fatty acid oxidation did not differ between the groups. Muscle fiber distribution, fiber size and capillary density do not contribute to the training effect. Dynamic training of this intensity does not affect muscle strength or strength endurance and muscle elctrophysiology, either.

The small sizes of the study groups set limitations for this conclusion. Possible changes may have been too small to be detected by this study. As a matter of fact, all studies evaluating the contribution of skeletal muscle to the improved exercise capacity in CHF have been small and, furthermore, previously the statistical comparison between the changes in the training and the control groups has been poorly reported. A large randomized controlled study is warranted. Furthermore, an investigation on the change in the nutritive capillary perfusion, which likely has a major contribution to the improved exercise capacity, would be valuable.


   Acknowledgements
 
We gratefully acknowledge the laboratorial assistance of Ms Marjut Appelqvist, Mrs Anja Kallio, Mrs Helena Taskinen, Mrs Jaana Tuomikangas and Mrs Päivi Tuominen. We warmly thank Docent Jan Dabek, M.D., for revising the English text. This study was supported by grants from Aarne Koskelo and Yrjö Jahnsson Foundations, the Academy of Finland, Finnish Foundation for Cardiovascular Research and the Finnish Ministry of Education.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 

  1. Wilson J., Fink L., Maris J., et al. Evaluation of energy metabolism in skeletal muscle of patients with heart failure with gated phosphorus-31 nuclear magnetic resonance. Circulation (1985) 71:57–62.[Abstract/Free Full Text]
  2. Massie B., Conway M., Yonge R., et al. Skeletal muscle metabolism in patients with congestive heart failure: relation to clinical severity and blood flow. Circulation (1987) 76:1009–1119.[Abstract/Free Full Text]
  3. Näveri H.K., Leinonen H., Kiilavuori K., Härkänen M. Skeletal muscle lactate accumulation and creatine phosphate depletion during heavy exercise in congestive heart failure; cause of limited exercise capacity. Eur Heart J (1997) 18:1937–1945.[Abstract/Free Full Text]
  4. Zelis R., Mason D.T., Braunwald E. A comparison of the effects of vasodilator stimuli on peripheral resistance vessels in normal subjects and in patients with congestive heart failure. J Clin Invest (1968) 47:960–970.[Web of Science][Medline]
  5. Kubo S., Rector T., Bank A., Williams R., Heifetz S. Endothelium-dependent vasodilation is attenuated in patients with heart failure. Circulation (1991) 84:1589–1596.[Abstract/Free Full Text]
  6. LeJemtel T., Maskin C., Lucido D., Chadwick B. Failure to augment limb blood flow in response to one-leg versus two-leg exercise in patients with severe heart failure. Circulation (1986) 74:245–251.[Abstract/Free Full Text]
  7. Zelis R., Flaim S. Alterations in vasomotor tone in congestive heart failure. Prog Cardiovasc Dis (1982) 24:437–459.[CrossRef][Web of Science][Medline]
  8. Wilson J., Martin J., Schwartz D., Ferraro N. Exercise intolerance in patients with chronic heart failure: role of impaired nutritive flow to skeletal muscle. Circulation (1984) 69:1079–1087.[Abstract/Free Full Text]
  9. Lipkin D., Jones D., Round J., PooleWilson P. Abnormalities of skeletal muscle in patients with chronic heart failure. Int J Cardiol (1988) 18:187–195.[CrossRef][Web of Science][Medline]
  10. Sullivan M., Green H., Cobb F. Skeletal muscle biochemistry and histology in ambulatory patients with long-term heart failure. Circulation (1990) 81:518–527.[Abstract/Free Full Text]
  11. Adamopoulos S., Coats A.J., Brunotte F., et al. Physical training improves skeletal muscle metabolism in patients with chronic heart failure. J Am Coll Cardiol (1993) 21:1101–1106.[Abstract]
  12. Belardinelli R., Georgiou D., Scocco V., Barstow T.J., Purcaro A. Low intensity exercise training in patients with chronic heart failure. J Am Coll Cardiol (1995) 26:975–982.[Abstract]
  13. Hambrecht R., Niebauer J., Fiehn E., et al. Physical training in patients with stable chronic heart failure: effects on cardiorespiratory fitness and ultrastructural abnormalities of leg muscle. J Am Coll Cardiol (1995) 25:1239–1249.[Abstract]
  14. Gordon A., TyniLenn R., Persson H., Kajser L., Hultman E., Sylvn C. Markedly improved skeletal muscle performance with local muscle training in patients with chronic heart failure. Clin Cardiol (1996) 19:568–574.[Web of Science][Medline]
  15. Hambrecht R., Fiehn E., Yu J., et al. Effects of endurance training on mitochondrial ultrastructure and fiber type distribution in skeletal muscle of patients with stable chronic heart failure. J Am Coll Cardiol (1997) 29:1067–1073.[Abstract]
  16. Newsholme E.A. Use of enzyme activity measurements in studies on the biochemistry of exercise. Int J Sports Med (1980) 1:100–102.[CrossRef]
  17. Holloszy J.O., Coyle E.F. Adaptations of skeletal muscle to endurance exercise and their metabolic consequences. J Appl Physiol Respir Environ Exercise Physiol (1984) 56:831–888.[Abstract/Free Full Text]
  18. Kiilavuori K., Sovijärvi A., Näveri H., Ikonen T., Leinonen H. Effect of physical training on exercise capacity and gas exchange in patients with chronic heart failure. Chest (1996) 110:985–991.[CrossRef][Web of Science][Medline]
  19. Lowry O.H., Rosebrough H.J., Farr A.L., Randall R.J. Protein measurement with the Folin Phenol reagent. J Biol Chem (1953) 193:265–275.[Web of Science]
  20. Härkänen M., Palkama A., Laasonen L. Effect of ethanol administration and nutritional state on glycogen phosphorylase activity in rat liver. Ann Med Exp Biol Fenn (1968) 46:568–575.[Web of Science][Medline]
  21. Härkänen M., Näveri H., Rehunen S., Kuoppasalmi K. Determination of metabolites and enzymes in muscle. Ann Clin Res (1982) 34:20–24.
  22. Lowry O., Rosebrough H., Farr A., Randall R. Enzyme patterns in single human muscle fibers. J Biol Chem (1953) 253:8269–8277.
  23. Deufel T., Wieland O.H. Sensitive assay of carnitine palmitoyl transferase activity in tissue homogenates with a modified spectrophotometric method for enzymatic carnitine determination. Clin Chim Acta (1983) 135:247–251.[CrossRef][Web of Science][Medline]
  24. Linssen W.H., Stegeman D.F., Joonsten E.M., van'tHof M.A., Binkhorst R.A., Notermans S.L. Variability and interrelationships of surface EMG parameters during local muscle fatigue. Muscle Nerve (1993) 16:849–856.[CrossRef][Web of Science][Medline]
  25. Stålberg E. Macro EMG. Muscle Nerve (1983) 6:619–630.[CrossRef][Web of Science][Medline]
  26. Mancini D.M., Walter G., Reichek N., et al. Contribution of skeletal muscle atrophy to exercise intolerance and altered muscle metabolism in heart failure. Circulation (1992) 85:1364–1373.[Abstract/Free Full Text]
  27. Mancini D.M., Coyle E., Coggan A., et al. Contribution of intrinsic skeletal muscle changes to 31P NMR skeletal muscle metabolic abnormalities in patients with chronic heart failure. Circulation (1989) 80:1338–1346.[Abstract/Free Full Text]
  28. Massie B.M., Simonini A., Sahgal P., Wells L., Dudley G.A. Relation of systemic and local muscle exercise capacity to skeletal muscle characteristics in men with congestive heart failure. J Am Coll Cardiol (1996) 27:140–145.[Abstract]
  29. Magnusson G., Gordon A., Kaijser L., et al. High intensity knee extensor training in patients with chronic heart failure; major skeletal muscle improvement. Eur Heart J (1996) 17:1048–1055.[Abstract/Free Full Text]
  30. Saltin B., Henriksson J., Nygaard E., Andersen P. Fiber types and metabolic potentials of skeletal muscles in sedentary man and endurance runners. In: The marathon: physiological, medical, epidemiological, and psychological studies vol. 301—Milvy P., ed. (1977) Annals of the New York Academy of Sciences. 3–29.
  31. Drexler H., Riede U., Münzel T., König H., Funke E., Just H. Alterations of skeletal muscle in chronic heart failure. Circulation (1992) 85:1751–1759.[Abstract/Free Full Text]
  32. Lindsay D., Lovegrove C., Dunn M., et al. Histological abnormalities of muscle from limb, thorax and diaphragm in chronic heart failure. Eur Heart J (1996) 17:1239–1250.[Abstract/Free Full Text]
  33. Holloszy J. Adaptations of muscular tissue to training. Prog Cardiovasc Dis (1976) 18:445–458.[CrossRef][Web of Science][Medline]
  34. Gollnick P., Armstrong R., Saltin B., Saubert C.W., Sembrowich W.L., Shepherd R.E. Effect of training on enzyme activity and fiber composition of human skeletal muscle. J Appl Physiol (1973) 34:107–111.[Free Full Text]
  35. Sullivan M., Higginbotham M., Cobb F. Exercise training in patients with severe left ventricular dysfunction. Circulation (1988) 78:506–515.[Abstract/Free Full Text]
  36. Demopoulos L., Bijou R., Fergus I., Jones M., Strom J., LeJemtel T. Exercise training in patients with severe congestive heart failure: enhancing peak aerobic capacity while minimizing the increase in ventricular wall stress. J Am Coll Cardiol (1997) 29:597–603.[Abstract]
  37. Kindig C., Musch T., Basaraba R., Poole D. Impaired capillary hemodynamics in skeletal muscle of rats in chronic heart failure. J Appl Physiol (1999) 87:652–660.[Abstract/Free Full Text]
  38. Sylvén C., Jansson E., Cederholm T., Hildebrand I.L., Beermann B. Skeletal muscle depressed calcium and phophofructokinase in chronic heart failure are upregulated with captopril-double-blind, placebo-controlled study. J Intern Med (1991) 229:171–174.[Web of Science][Medline]
  39. Sullivan M., Green H., Cobb F. Altered skeletal muscle metabolic response to exercise in chronic heart failure. Circulation (1991) 84:1597–1607.[Abstract/Free Full Text]
  40. Schaufelberger M., Eriksson B.O., Held P., Swedberg K. Skeletal muscle metabolism during exercise in patients with chronic heart failure. Heart (1996) 76:29–34.[Abstract/Free Full Text]
  41. Koch M., Douard H., Broustet J.P. The benefit of graded physical exercise in chronic heart failure. Chest (1992) 101:231S–235S.[Medline]
  42. Harrington D., Anker S., Chua T., et al. Skeletal muscle function and its relation to exercise tolerance in chronic heart failure. J Am Coll Cardiol (1997) 30:1758–1764.[Abstract]
  43. Minotti J., Pillay P., Chang L., Wells L., Massie B. Neurophysiological assessment of skeletal muscle fatigue in patients with congestive heart failure. Circulation (1992) 86:903–908.[Abstract/Free Full Text]
  44. Harridge S., Magnusson G., Gordon A. Skeletal muscle contractile characteristics and fatigue resistance in patients with chronic heart failure. Eur Heart J (1996) 17:895–901.

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