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CLINICAL RESEARCH: HEART FAILURE/TRANSPLANTATION

Preserved response of mitochondrial function to short-term endurance training in skeletal muscle of heart transplant recipients

Joffrey Zoll, PhD^*,*, Benoit N’Guessan, BS^*, Florence Ribera, PhD^*, Eliane Lampert, MD^*, Dominique Fortin, Vladimir Veksler, MD, PhD, Xavier Bigard, MD, PhD, Bernard Geny, MD, PhD^*, Jean Lonsdorfer, MD, PhD^*, Renée Ventura-Clapier, PhD and Bertrand Mettauer, MD, PhD^*

^* Service de Physiologie Clinique et des Explorations Fonctionnelles, Département de Physiologie, Faculté de Médecine, Strasbourg, France
Cardiologie Cellulaire et Moléculaire, U-446 INSERM, Faculté de Pharmacie, Université Paris-Sud, Châtenay-Malabry, France
Unité de Bioénergétique, CRSSA, La-Tronche Cedex, France

Manuscript received January 23, 2003; revised manuscript received March 19, 2003, accepted March 27, 2003.

^* Reprint requests and correspondence: Dr. Joffrey Zoll, Département de Physiologie, Faculté de Médecine, 11, rue Humann, 67000 Strasbourg, France.
Zolljoffrey{at}yahoo.com

	Abstract

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OBJECTIVES: We sought to determine whether intrinsic mitochondrial function and regulation were altered in heart transplant recipients (HTRs) and to investigate the response of mitochondrial function to six-week endurance training in these patients.

BACKGROUND: Despite the normalization of central oxygen transport during exercise, HTRs are still characterized by limited exercise capacity, which is thought to result from skeletal muscle metabolic abnormalities.

METHODS: Twenty HTRs agreed to have vastus lateralis biopsies and exercise testing: before and after training for 12 of them and before and after the same control period for eight subjects unwilling to train. Mitochondrial respiration was evaluated on saponin-permeabilized muscle fibers in the absence or presence (maximum respiration rate [V_max]) of saturating adenosine diphosphate.

RESULTS: Mitochondrial function was preserved at the level of sedentary subjects in untrained HTRs, although they showed 28 ± 5% functional aerobic impairment (FAI). After training, V_max, citrate synthase, cytochrome c oxidase, and mitochondrial creatine kinase (CK) activities were significantly increased by 48%, 40%, 67%, and 53%, respectively (p < 0.05), whereas FAI decreased to 12 ± 5% (p < 0.01). The control of mitochondrial respiration by creatine and mitochondrial CK was also improved (p < 0.01), suggesting that phosphocreatine synthesis and transfer by the mitochondrial CK become coupled to oxidative phosphorylation, as shown in trained, healthy subjects.

CONCLUSIONS: In HTRs, the mitochondrial properties of skeletal muscle were preserved and responded well to training, reaching values of physically active, healthy subjects. This suggests that, in HTRs, immunosuppressive drugs do not alter the intrinsic muscle oxidative capacities and that the patients’ physical handicap results from nonmitochondrial mechanisms.

Abbreviations and Acronyms   ADP   adenosine diphosphate   CHF   congestive heart failure   CK   creatine kinase   CsA   cyclosporin A   FAI   functional aerobic impairment   HTRs   heart transplant recipients   MTP   maximum tolerated power   MyHC   myosin heavy chain   T   trained subjects   UT   untrained subjects   Vmax   maximum respiration rate   VO2   oxygen consumption   VT   ventilatory threshold

On the other hand, as deconditioning may represent a major factor of physical handicap after transplantation, numerous studies have addressed the effects of short- and long-term endurance training in HTRs (12–14) and have shown beneficial increases of exercise capacity (12,15). Using ultrastructural morphometry, we observed that short-term endurance training was able to improve the total and subsarcolemmal mitochondrial volume density within the skeletal muscle but did not change the already reduced capillary network (7). Although we and others have recently shown that endurance training induces enhancement of both muscle oxidative capacity and mechanisms of respiratory control in skeletal muscles of healthy subjects (16–18), the response of mitochondrial function to endurance training needs to be determined in HTRs. As we have demonstrated that HTRs’ exercise capacity after training remained lower than that of untrained, normal, sedentary subjects (7), the response to training of the skeletal muscle mitochondrial function could be altered in HTRs. Therefore, in an effort to sort out the contribution of intrinsic mitochondrial properties to exercise limitation in HTRs under standard immunosuppressive treatment, we assessed the skeletal muscle oxidative capacity and its regulation and investigated the adaptation of mitochondrial function to a six-week endurance training program. To this end, mitochondrial respiration was studied in situ by a method recently adapted to human samples (16,18,19), that is based on selective permeabilization of the sarcolemma, keeping mitochondria in their intracellular environment (20).

	Methods

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Subjects.   Twenty-three HTRs (19 men and 4 women) were enrolled in the study. All subjects gave their written, informed consent to the study, which was approved by the local institutional ethics committee. The HTRs were free of significant rejection or infection and were enrolled in the training program 9 ± 1 month after grafting. Before surgery, our patients were in NYHA class III or IV. As part of their immunosuppressive regimen they received oral CsA (Neoral, Novartis, Basel, Switzerland; 252 ± 19 mg/day) and prednisone (18 ± 4 mg/day). Some patients were treated with antihypertensive therapy, calcium channel blockers, and furosemide. Beyond the three-week standard immediate postoperative rehabilitation, none of them were enrolled in any regular physical training program but resumed their professional or private activities at the time of the study. All patients were in NYHA class I or II at the time of enrollment. Three patients had to be withdrawn from the study: one for acute rejection that resolved but temporarily prevented the patient from exercising; one for mild rhabdomyolysis; and one for sciatic nerve syndrome. Of the remaining 20 patients, 12 completed a supervised six-week endurance training program (T group), whereas the other eight untrained subjects (UT group) did not wish to engage in any form of physical training and were considered as control subjects for spontaneous changes.

Experimental design
Maximum exercise testing
Patients underwent a graded maximum exercise test in the upright position, using an electronically braked bicycle ergometer. Throughout exercise, expired gas analysis was performed using a breath-by-breath metabolic cart that yielded oxygen consumption (VO₂) and the ventilatory threshold (VT) by V-slope analysis (21). The work load was increased by 20 W every 2 min until volitional exhaustion, to yield the maximum tolerated power (MTP) and peak VO₂. In patients undergoing training, lactate microsamples were taken at the earlobe at the end of exercise and every minute during the first 5 min of passive recovery, with the maximum recorded lactate value being defined as peak lactate. In the T group after training, a lactate sample was taken when the step at the pretraining maximum work rate was completed. The functional aerobic impairment (FAI) was calculated as follows: FAI = ([predicted peak VO₂ – observed peak VO₂]/predicted peak VO₂) x 100, used to evaluate the limited exercise capacity of HTRs (4). Predicted peak VO₂ was calculated using Hansen’s formulae (21).

Training protocol
Training included three 45-min sessions per week for six weeks of modified interval training, as previously described (7). Each session consisted of nine successive 5-min bouts. During each exercise bout, a 4-min moderate base work load was followed by 1 min of heavy peak level work load. Bases and peaks were initially set at the individual VT and at 90% of MTP, respectively. Target work rates were adjusted to maintain the exercise heart rate during training at base and peak levels reached during the first session.

Skeletal muscle biopsy
Vastus lateralis muscle was obtained by the Bergström biopsy technique under local anesthesia. One part was immediately frozen in liquid nitrogen for enzymatic and myosin heavy chain (MyHC) studies. Thin bundles were immediately dissected in iced-cold relaxing solution containing (in mmol/l) 10 EGTA-calcium buffer (free Ca²⁺ concentration, 100 nmol/l), 1 free Mg²⁺, 20 taurine, 0.5 dithiothreitol, 20 imidazole (pH 7.1), 5 MgATP, and 15 phosphocreatine, at 160 ionic strength (potassium methanesulfonate) and permeabilized for 30 min with 50 µg/ml saponin for respiration studies.

Mitochondrial respiration, biochemical studies, and myosin determination
Oxidative capacity and mitochondrial regulation of vastus lateralis muscle fibers were studied in situ in freshly saponin-skinned fibers, as previously described (22,23). Briefly, respiratory rates were determined with a Clark electrode (Strathkelvin Instruments, Glasgow, U.K.) in the presence of 2 mmol/l adenosine diphosphate (ADP) and normalized to fiber dry weight. The ADP-stimulated respiration (V_ADP) above basal VO₂ was plotted as a function of ADP. The apparent Michaelis-Menten constant (K_m) for ADP, inversely proportional to ADP sensitivity, and V_ADP were calculated using a nonlinear fitting of the Michaelis-Menten equation. The maximum respiration rate (V_max) is expressed as: V_ADP + basal VO₂. It characterizes the oxidative capacity of the muscle.

Citrate synthase, cytochrome c oxidase, creatine kinase (CK), and lactate dehydrogenase activities were assessed by standard spectrophotometric methods. Lactate dehydrogenase and CK isoenzymes were separated using 1% agarose gel electrophoresis, as described (23,24). Isoforms of MyHC were separated by sodium dodecyl sulfate/polyacrylamide gel electrophoresis (25).

Statistical analysis
Data are expressed as the mean value ± SEM. The effect of training or the spontaneous evolution in the untrained group was assessed by means of two-way analysis of variance for repeated measures (one-factor repetition), whereas differences between groups were analyzed using the unpaired Student t test. The level of significance was set at p < 0.05.

	Results

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Subject characteristics and exercise testing.   Age, weight, and height were similar between the UT and T groups of HTRs (Table 1). Table 2 shows the parameters of aerobic performance during the incremental exercise test. The calculated FAI was 24 ± 5% in trained patients before training and 28 ± 6% in untrained patients initially. After training, peak VO₂ (+18%, p < 0.01), VO₂ at VT (+20%, p < 0.05), and MTP values (+19%, p < 0.01) were all increased in the trained group. Therefore, the FAI decreased to only 12 ± 5% (p < 0.01). Lactate peak values were identical before and after training (Table 2), whereas the blood lactate concentration at the work load corresponding to pretraining MTP was reduced after training (p < 0.01). There were no changes in any of these parameters of aerobic performance during the same follow-up period in the UT group.

View larger version (32K): [in this window] [in a new window]   Figure 1 Parameters of mitochondrial respiration. Muscle fiber bundles were taken from the vastus lateralis of heart transplant recipients before and after training in the trained (T) group and at the same follow-up period in the untrained (UT) group. (A) Basal and maximum respiration (Vmax) (expressed in µmol O2/min per g dry weight) were measured in saponin-skinned fibers. (B) The acceptor control ratio (ACR) (Vmax/basal VO2). Data are expressed as the mean value ± SEM. *p < 0.05 vs. T before training.

View larger version (21K): [in this window] [in a new window]   Figure 2 Apparent Michaelis-Menten constant (Km) for adenosine diphosphate (ADP)-stimulated respiration in the absence or presence of creatine. The Km (µmol/l) without creatine was increased after training (**p < 0.01). The addition of creatine significantly decreased the Km, but only after training (p < 0.01 vs. Km without creatine). Dotted bars = untrained (UT) group before training; bars with diagonal lines = UT group after training; open bars = trained (T) group before training; solid bars = T group after training.

	Discussion

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Mitochondrial function in untrained HTRs
After heart transplantation, the persistence of an increased phosphocreatine breakdown for a given work rate and decreased high-energy phosphate resynthesis rates, which even tends to further worsen early after transplantation, raised the question of impaired mitochondrial function after transplantation (3). However, earlier we found no difference in the ultrastructural mitochondrial volume density of the vastus lateralis muscle between untrained HTRs and sedentary, healthy subjects (26). The present results extend these data by showing that the muscle’s mitochondrial function and regulation are preserved in HTRs and were maintained similar to that of sedentary, healthy subjects (16,17). This is also consistent with preserved intrinsic mitochondrial function in CHF patients before transplantation (16).

Mitochondrial function of trained HTRs
Because the persisting physical handicap after transplantation is partly due to deconditioning and because CsA, the major immunosuppressive drug given in HTRs, has been shown in animal studies to induce phenotypic changes and to attenuate the normal responses to muscular growth by inhibiting the nuclear factor of activated T cells pathway (27,28), the question of whether mitochondrial properties adequately respond to training is of clinical relevance. We report here that in HTRs, short-term endurance training markedly increases the muscle’s oxidative capacity and enzyme activities, reaching values found in trained, healthy subjects whose peak VO₂ is twice as high (16). In normal subjects, Walsh et al. (18) obtained 20% and 38% increases in peak VO₂ and V_max, respectively, as a result of six-week training by 60-min sessions at 70% of peak VO₂, whereas in HTRs, we observed 17% and 48% increases of peak VO₂ and V_max, respectively, as a result of the same training duration with 45-min sessions but with an interval training protocol. Thus, we obtained similar increases in exercise capacity and higher increases in V_max in HTRs, despite shorter session durations. This is consistent with the well-known higher beneficial effects of training in the most detrained subjects for any given intensity (29). In addition, the regulation of mitochondrial respiration also greatly responded to training. As previously described (30), mitochondrial sensitivity to ADP is characteristic of the metabolic phenotype of muscle, being high in oxidative muscles (300 to 600 µmol/l) and low in glycolytic muscles (10 to 50 µmol/l). Indeed, there was a decrease in the mitochondrial sensitivity to ADP toward values already found in trained, healthy subjects (16). Moreover, this sensibility of mitochondria to ADP significantly increased in the presence of creatine only after training, suggesting an efficient mitochondrial CK coupling with oxidative phosphorylation and the appearance of coupled energy transfer pathways through the CK shuttle. Thus, the present results suggest that as in athletic, normal subjects (17), the mitochondrial CK system is likely to play an important role in the control of mitochondrial respiration in the skeletal muscle of trained HTRs. This allows the connection between energy production by oxidative phosphorylation and energy utilization through cytosolic CK and CK bound to myofilaments or the sarcoplasmic reticulum. This servo-control of energy production by mitochondria appears adapted for sustained contractile activity of endurance exercise (17). On the other hand, the acceptor control ratio was not significantly increased in trained HTRs, as was the case in athletic subjects compared with sedentary subjects, suggesting that long-term training is probably necessary to significantly improve mitochondrial efficiency (17). The same holds true for MyHC composition. It is possible that neither the duration nor the intensity of the exercise performed by our patients after transplantation was sufficient to produce significant MyHC changes, because adaptive myosin changes to endurance training are known to be late and inconsistent (31).

Clinical implications
The present study shows, for the first time, that skeletal muscle fibers of HTR patients exhibit a normal mitochondrial profile and normal expected responses to physical training, despite immunosuppressive therapy with CsA. Administration of CsA at high dosages decreases mitochondrial respiration in vitro (8,11) and in vivo (9,10) and alters the MyHC and metabolic profile of animal skeletal muscle (28). As we demonstrated that these muscular deleterious effects are due to the vehicle and not to the active molecule (10,11), it is likely that at the clinical doses of oral CsA, the toxic effects of the vehicle on mitochondrial function are not detectable in humans. Because the beneficial changes of training on mitochondrial function only partially translated into an increase in exercise capacity, the mechanisms of limitation likely take place upstream from the mitochondria and may further operate after training. Among these mechanisms, a limited oxygen and substrate delivery resulting from the reduced capillary network, which remained unchanged after training (6,7), might contribute to limit maximum exercise performance. In addition, chronotropic incompetence due to graft denervation contributes to build up a greater oxygen deficit for a given work rate (32), rather than impairing the maximum exercise heart rate (33). Moreover, the beneficial effects of training on endothelial function might be offset by immunosuppressive treatment (34,35). Indeed, CsA has been shown to decrease endothelium-dependent vasodilation, which might decrease oxygen delivery to mitochondria at the microvascular level (34). On the other hand, development of muscle atrophy is a well-known complication of therapy with glucocorticoids. Horber et al. (36) showed that prednisone at a mean dose of 10 mg/day was associated with a decreased number of capillaries and fibers of the thigh muscle but did not abrogate the exercise-induced improvement of skeletal muscle in renal transplant patients. Indeed, Renlund et al. (37) found that the corticosteroid dose predicted exercise duration and peak VO₂ in HTRs. Our patients were treated with prednisone (18 ± 4 mg/day), and it cannot be completely ruled out that this treatment might have induced muscle atrophy, contributing to limit their exercise capacity, even though in a previous report (7), we did not find any significant change in the thigh muscle area in a similar population of patients.

Conclusions
In HTRs, the skeletal muscle mitochondrial function is normal nine months after grafting and dramatically improves after short-term endurance training, with the emergence of an efficient coupling of mitochondrial CK with ADP rephosphorylation. Thus, our data suggest, for the first time, that: 1) the mitochondrial toxicity of immunosuppressive therapy, especially CsA, is negligible in the clinical field and does not alter mitochondrial response to training, at least within the first year after transplantation; and 2) the mechanisms leading to the persisting physical handicap after heart transplantation is independent of muscular intrinsic metabolic capacities but proceeds from mechanisms upstream from the mitochondria, even more so after training.

	Acknowledgments

 
We are indebted to Prof. R. Fischmeister and Dr. E. Epailly for continuous support and to our volunteers for their enthusiastic participation.

	Footnotes

 
This study was supported by INSERM-PROGRES and Fondation de France and Fondation pour la Recherche Médicale grants. Dr. Ventura-Clapier is supported by the Centre National de la Recherche Scientifique. Joffrey Zoll and Benoit N’Guessan contributed equally to this work.

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