Browsing by Author "Zoll, J"
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Item ACE inhibition prevents myocardial infarction-induced skeletal muscle mitochondrial dysfunction(Journal of Applied Physiology, 2006) Zoll, J; Monassier, L; Garnier, A; N'Guessan, B; Mettauer, B; Veksler, V; Piquard, F; Ventura-Clapier, R; Geny, BHeart failure is associated with alterations in cardiac and skeletal muscle energy metabolism resulting in a generalized myopathy. We investigated the molecular and cellular effects of angiotensin-converting enzyme inhibition (ACEi) on skeletal muscle metabolism in infarcted animals. Myocardial infarction (MI) was obtained by left descending coronary artery ligation. Sham, MI, and MI-treated rats (perindopril, 2 mg.kg(-1).day(-1) given 7 days after MI) were studied 1 and 4 mo after surgery. Oxygen consumption of white gastrocnemius (Gas) muscle was studied in saponin-permeabilized fibers, using the main substrates of mitochondrial respiration. mRNA expression of nuclear factors (PGC-1alpha, NRF-2alpha, and mtTFA), involved in the transcription of mitochondrial proteins, and of MCIP1, a marker of calcineurin activation, were also determined. Echocardiographic left ventricular fractional shortening was reduced in both MI and perindopril group after 1 and 4 mo, whereas systemic blood pressure was reduced by 16% only in the MI group after 4 mo. The capacity of Gas to oxidize glutamate-malate, glycerol-triphosphate, or pyruvate (-30%, P < 0.01; -32%, P < 0.05; -33%, P < 0.01, respectively), was greatly decreased. Furthermore, PGC-1alpha (-54%), NRF-2alpha (-45%), and MCIP1 (-84%) gene expression were significantly downregulated. ACEi improved survival, left ventricular function, and blood pressure. Perindopril protected also totally the Gas mitochondrial function and preserved the mRNAs concentration of the mitochondrial transcriptional factors. Moreover, PGC-1alpha correlated with Gas oxidative capacity (r = 0.48), mitochondrial cytochrome-c oxidase (r = 0.65), citrate synthase (r = 0.45) activities, and MCIP1 expression (r = 0.44). Thus ACEi totally prevented MI-induced alterations of skeletal muscle mitochondrial function and protein expression, halting the development of this metabolic myopathy.Item ). Control by circulating factors of mitochondrial function and transcription cascade in heart failure. Circulation(Heart Failure, 2009) Garnier, A; Zoll, J; Fortin, D; N'Guessan, B; Lefebvre, F; Geny, B; Mettauer, B; Veksler, V; Ventura-Clapier, RBACKGROUND: Evidence is emerging to support the concept that the failing heart is "energy depleted" and that defects in energy metabolism are important determinants in the development and the progression of the disease. We have shown previously that depressed mitochondrial function in cardiac and skeletal muscles in chronic heart failure is linked to decreased expression of the gene encoding transcriptional proliferator-activated receptor-gamma coactivator-1alpha, the inducible regulator of mitochondrial biogenesis and its transcription cascade, leading to altered expression of mitochondrial proteins. However, oxidative capacity of the myocardium of patients treated for chronic heart failure and pathophysiological mechanisms of mitochondrial dysfunction are still largely unknown. METHODS AND RESULTS: In patients with chronic heart failure treated with angiotensin-converting enzyme inhibition, cardiac oxidative capacity, measured in saponin-permeabilized fibers, was 25% lower, and proliferator-activated receptor-gamma coactivator-1alpha protein content was 34% lower compared with nonfailing controls. In a rat model of myocardial infarction, angiotensin-converting enzyme inhibition therapy was only partially able to protect cardiac mitochondrial function and transcription cascade. Expression of proliferator-activated receptor-gamma coactivator-1alpha and its transcription cascade were evaluated after a 48-hour exposure of cultured adult rat ventricular myocytes to endothelin-1, angiotensin II, aldosterone, phenylephrine, or isoprenaline. Endothelin-1 (-30%) and, to a lesser degree, angiotensin II (-20%) decreased proliferator-activated receptor-gamma coactivator-1alpha mRNA content, whereas other hormones had no effect (phenylephrine) or even increased it (aldosterone, isoprenaline). CONCLUSIONS: Taken together, these results show that, despite angiotensin-converting enzyme inhibition treatment, oxidative capacity is reduced in human and experimental heart failure and that endothelin-1 and angiotensin II could be involved in the downregulation of the mitochondrial transcription cascade.Item Coordinated changes in mitochondrial function and biogenesis in healthy and diseased human skeletal muscle(FASEB Journal, 2005) Garnier, A; Fortin, D; Zoll, J; N'Guessan, B; Mettauer, B; Lampert, E; Veksler, V; Ventura-Clapier, RWe examined the transcriptional signaling cascade involved in the changes of mitochondrial biogenesis and mitochondrial function of skeletal muscle and of the exercise capacity of humans in response to long-term physical activity and chronic heart failure (CHF). Biopsy samples of vastus lateralis muscle were obtained from 18 healthy subjects with different fitness levels (assessed by maximal oxygen uptake, VO2 peak). We compared 9 sedentary subjects with 10 CHF patients undergoing transplantation. Muscle oxidative capacity was measured in permeabilized fibers (Vmax). Transcript levels of target genes were quantified by RT-PCR. In healthy subjects, VO2 peak was linearly related to Vmax (P<0.01) and to the gene expression of mitochondrial proteins and of the coactivator PGC-1alpha and its downstream transcription factors. A coordinate increase in PGC-1alpha and mRNA levels of proteins involved in degradation, fusion, and fission of mitochondria was observed associated with calcineurin activation. Despite decreased VO2 peak, in CHF patients skeletal muscles showed preserved Vmax in accordance with preserved markers and transcription factors of mitochondrial biogenesis and dynamics, with no calcineurin activation. The results provide strong support for a central role for PGC-1alpha and calcineurin activation in mitochondrial biogenesis in healthy and diseased human skeletal muscles.Item Effect of chronic pre-treatment with angiotensin converting enzyme inhibition on skeletal muscle mitochondrial recovery after ischemia/reperfusion(Fundamental and Clinical Pharmacology, 2010) Thaveau, F; Zoll, J; Bouitbir, J; N'Guessan, B; Plobner, P; Chakfe, N; Kretz, J.G; Richard, R; Piquard, F; Geny, BImpaired skeletal muscle energetic participates in peripheral arterial disease (PAD) patient's morbidity and mortality. Angiotensin converting enzyme inhibition (ACEi), cornerstone for pharmacologic risk factor management in PAD patients, might also be interesting by protecting skeletal muscle energetic. We therefore determined whether chronic ACEi might reduce ischemia-induced mitochondrial respiratory chain dysfunction in the frequent setting of hindlimb ischemia-reperfusion. Ischemic legs of rats submitted to 5 h ischemia induced by a rubber band tourniquet applied on the root of the hindlimb followed by reperfusion without (IR, n = 11) or after ACEi (n = 14; captopril 40 mg/kg per day during 28 days before surgery) were studied and compared to that of sham-operated animals (n = 11). The effect of ACEi on the non-ischemic contralateral leg was also determined in the ACEi group. Maximal oxidative capacities (V(max)) and complexes I, II and IV activities of the mitochondrial respiratory chain of the gastrocnemius muscle were determined using glutamate-malate, succinate and TMPD-ascorbate substrates. Arterial blood pressure was significantly decreased after ACEi (124 +/- 2.8 vs. 108 +/- 4.19 mmHg; P = 0.01). Ischemia-reperfusion reduced V(max) (4.4 +/- 0.4 vs. 8.7 +/- 0.5 micromol O2/min/g dry weight, -49%, P < 0.001), affecting mitochondrial complexes I, II and IV activities. ACEi failed to modulate ischemia-induced dysfunction (V(max) 5.1 +/- 0.7 micromol O2/min/g dry weight) or the non-ischemic contralateral muscle respiratory rate. Ischemia-reperfusion significantly impaired the mitochondrial respiratory chain I, II and IV complexes of skeletal muscle. Pharmacologic pre-treatment with ACEi did not prevent or increase such alterations. Further studies might be useful to improve the pharmacologic conditioning of PAD patients needing arterial revascularization.Item Evaluation of quantitative and qualitative aspects of mitochondrial function in human skeletal and cardiac muscles(Molecular and Cellular Biochemistry, 2004) N'Guessan, B; Zoll, J; Ribera, F; Ponsot, E; Lampert, E; Ventura-Clapier, R; Veksler, V; Mettauer, BTechniques and protocols of assessment of mitochondrial properties are of physiological and physiopathological important significance. A precise knowledge of the advantages and limitations of the different protocols used to investigate the mitochondrial function, is therefore necessary. This report presents examples of how the skinned (or permeabilized) fibers technique could be applied for the polarographic determination of the actual quantitative and qualitative aspects of mitochondrial function in human muscle samples. We described and compared the main available respiration protocols in order to sort out which protocol seems more appropriate for the characterization of mitochondrial properties according to the questions under consideration: quantitative determination of oxidative capacities of a given muscle, characterization of the pattern of control of mitochondrial respiration, or assessment of a mitochondrial defect at the level of the respiratory chain complexes. We showed that while protocol A, using only two levels of the phosphate acceptor adenosine diphosphate (ADP) concentration and the adjunction of creatine, could be used for the determination of quantitative changes in very small amount of muscle samples, the ADP sensitivity of mitochondrial respiration was underestimated by this protocol in muscles with high oxidative capacities. The actual apparent Km for ADP and the role of functional activation of miCK in ATP production and energy transfer in oxidative muscles, are well-assessed by protocol B (in the absence of creatine) together with protocol C (in the presence of creatine) that use increasing concentrations of ADP ranging from 2.5-2000 microM. Protocol D is well-adapted to investigate the potential changes at different levels of the respiratory chain, by the use of specific substrates and inhibitors. As can be seen from the present data and the current review of previous reports in the literature, a standardization of the respiration protocols is needed for useful comparisons between studies.Item An impaired cardiodynamic phase contributes to the abnormal Vo2 kinetics at exercise onset in both congestive heart failure and heart transplant patients but results from differing mechanisms(Transplantation Proceedings, 2001) M'Bouh, S; Bellmont, S; Lampert, E; Epailly, E; Zoll, J; N'Guessan, B; Mettauer, BItem Journal of Applied Physiology(Journal of Applied Physiology, 2006) Ponsot, E; Dufour, S.P.; Zoll, J; Doutrelau, S; N'Guessan, B; Geny, B; Hoppeler, H; Lampert, E; Mettauer, B; Ventura-Clapier, R; Richard, RThis study investigates whether adaptations of mitochondrial function accompany the improvement of endurance performance capacity observed in well-trained athletes after an intermittent hypoxic training program. Fifteen endurance-trained athletes performed two weekly training sessions on treadmill at the velocity associated with the second ventilatory threshold (VT2) with inspired O2 fraction = 14.5% [hypoxic group (Hyp), n = 8] or with inspired O2 fraction = 21% [normoxic group (Nor), n = 7], integrated into their usual training, for 6 wk. Before and after training, oxygen uptake (VO2) and speed at VT2, maximal VO2 (VO2 max), and time to exhaustion at velocity of VO2 max (minimal speed associated with VO2 max) were measured, and muscle biopsies of vastus lateralis were harvested. Muscle oxidative capacities and sensitivity of mitochondrial respiration to ADP (Km) were evaluated on permeabilized muscle fibers. Time to exhaustion, VO2 at VT2, and VO2 max were significantly improved in Hyp (+42, +8, and +5%, respectively) but not in Nor. No increase in muscle oxidative capacity was obtained with either training protocol. However, mitochondrial regulation shifted to a more oxidative profile in Hyp only as shown by the increased Km for ADP (Nor: before 476 +/- 63, after 524 +/- 62 microM, not significant; Hyp: before 441 +/- 59, after 694 +/- 51 microM, P < 0.05). Thus including hypoxia sessions into the usual training of athletes qualitatively ameliorates mitochondrial function by increasing the respiratory control by creatine, providing a tighter integration between ATP demand and supply.Item Mitochondrial electron transport chain function is enhanced in inspiratory muscles of patients with chronic obstructive pulmonary disease(American Journal of Respiratory and Critical Care Medicine, 2003) Ribera, F; N'Guessan, B; Zoll, J; Fortin, D; Serrurier, B; Mettauer, B; Bigard, X; Ventura-Clapier, R; Lampert, EIn chronic obstructive pulmonary disease, inspiratory muscles face increased resistive and elastic workloads and therefore increased energy requirements. The adaptive response of these muscles to this higher energy demand includes increased oxidative enzymes and changes in contractile protein expression but the consequences on mitochondrial function and energy metabolism have not been assessed so far. We investigated the in situ properties of the mitochondria of costal diaphragm and external intercostal muscles using the skinned fiber technique in 9 emphysematous and 11 age-matched control patients. Biopsies obtained during thoracic surgery were placed in an oxygraphic chamber to measure maximal oxygen uptake. We observed that the maximal oxidative capacity of diaphragm and external intercostal muscles increased significantly in the emphysematous group compared with the control group (+135 and +37%, respectively). Significant correlations were found between the maximal oxidative capacity and patients' pulmonary indexes of obstruction (diaphragm: r = -0.637, intercostal: r = -0.667, p < 0.005) and hyperinflation (diaphragm: r = 0.639, p < 0.003, intercostal: r = 0.634, p < 0.01). Slow myosin heavy chain isoform increased in the diaphragm of the emphysematous group, with significant relationships between indexes of obstruction and hyperinflation and activities of biochemical mitochondrial markers. Thus, severe emphysema was associated with increased mitochondrial capacity and efficiency in the inspiratory muscles, supporting an endurance training-like effect.Item Muscular mitochondrial function in amyotrophic lateral sclerosis is progressively altered as the disease develops: A temporal study in man(Experimental Neurology, 2006) Echaniz-Laguna, A; Zoll, J; Ponsot, E; N'Guessan, B; Tranchant, C; Loeffler, J.P.; Lampert, EWe performed repeated analysis of mitochondrial respiratory function in skeletal muscle (SM) of patients with early-stage sporadic amyotrophic lateral sclerosis (SALS) to determine whether mitochondrial function was altered as the disease advanced. SM biopsies were obtained from 7 patients with newly diagnosed SALS, the same 7 patients 3 months later, and 7 sedentary controls. Muscle fibers were permeabilized with saponin, then skinned and placed in an oxygraphic chamber to measure basal and maximal adenosine diphosphate (ADP)-stimulated respiration rates and to assess mitochondrial regulation by ADP. We found that the maximal oxidative phosphorylation capacity of muscular mitochondria significantly increased, and muscular mitochondrial respiratory complex IV activity significantly decreased as the disease advanced. This temporal study demonstrates for the first time that mitochondrial function in SM in human SALS is progressively altered as the disease developsItem Oxidative capacities of cardiac and skeletal muscles of heart transplant recipients: Mitochondrial effects of cyclosporin-A and its vehicle cremophor-EL(Fundamental and Clinical Pharmacology, 2012) N'Guessan, B.B.; Sanchez, H; Zoll, J; Ribera, F; Dufour, S; Lampert, E; Kindo, M; Geny, B; Ventura-Clapier, R; Mettauer, BChronic immunosuppressive treatment was suspected to alter maximal muscle oxidative capacity (V(max) ) of heart transplant recipients, leading to a limitation of their exercise tolerance. It remains undefined whether the mitochondrial respiratory chain (MRC) of right ventricle (RV) and vastus lateralis (VL) muscles were altered by immunosuppressants and/or their vehicles. V(max) was measured polarographically in saponin-skinned fibres of RV and VL biopsies of patients and compared with V(max) of healthy VL and myocardium. Effects of increasing concentrations (1-10-100 μM) of Sandimmune(®) , its vehicle, Cyclosporine (CsA) in ethanol (EtOH), or EtOH alone were tested. The vehicle's effects on MRC complexes were investigated using specific substrates and inhibitors. Ten months after grafting, V(max) of RV and VL of immunosuppressed patients were similar to their V(max) at time of transplantation and to that of control tissues. In Vitro, Sandimmune(®) significantly decreased V(max) while CsA in EtOH or EtOH exerted small and similar effects. Effects of the vehicle were higher than (RV) or identical to (VL) those of Sandimmune(®) . The sites of action of the vehicle on MRC were located on complexes I and IV. While unchanged under chronic immunosuppressive therapy, V(max) of RV and VL muscles was depressed by acute exposure to intravenous Sandimmune(®) in vitro, an effect attributed to its vehicle by inhibition of complexes I and IV of the MRC. This work provides an in vitro proof of a toxic effect on the mitochondria respiratory chain of the vehicle used in the intravenous formulation of Sandimmune(®) but with no clinical consequences in chronically immunosuppressed patients.Item Physical activity changes the regulation of mitochondrial respiration in human skeletal muscle(Journal of Physiology, 2002) Zoll, J; Sanchez, H; N'Guessan, B; Ribera, F; Lampert, E; Bigard, X; Mettauer, BThis study explores the importance of creatine kinase (CK) in the regulation of muscle mitochondrial respiration in human subjects depending on their level of physical activity. Volunteers were classified as sedentary, active or athletic according to the total activity index as determined by the Baecke questionnaire in combination with maximal oxygen uptake values (peak V(O2), expressed in ml min(-1) kg(-1)). All volunteers underwent a cyclo-ergometric incremental exercise test to estimate their peak V(O2) and V(O2) at the ventilatory threshold (VT). Muscle biopsy samples were taken from the vastus lateralis and mitochondrial respiration was evaluated in an oxygraph cell on saponin permeabilised muscle fibres in the absence (V(0)) or in the presence (V(max)) of saturating [ADP]. While V(0) was similar, V(max) differed among groups (sedentary, 3.7 +/- 0.3, active, 5.9 +/- 0.9 and athletic, 7.9 +/- 0.5 micromol O2 min(-1) (g dry weight)(-1)). V(max) was correlated with peak V(O2) (P < 0.01, r = 0.63) and with V(T) (P < 0.01, r = 0.57). There was a significantly greater degree of coupling between oxidation and phosphorylation (V(max)/V(0)) in the athletic individuals. The mitochondrial K(m) for ADP was significantly higher in athletic subjects (P < 0.01). Mitochondrial CK (mi-CK) activation by addition of creatine induced a marked decrease in K(m) in athletic individuals only, indicative of an efficient coupling of mi-CK to ADP rephosphorylation in the athletic subjects only. It is suggested that increasing aerobic performance requires an enhancement of both muscle oxidative capacity and mechanisms of respiratory control, attesting to the importance of temporal co-ordination of energy fluxes by CK for higher efficacy.Item Preserved response of mitochondrial function to short-term endurance training in skeletal muscle of heart transplant recipients(Journal of the American College of Cardiology, 2003) Zoll, J; N'Guessan, B; Ribera, F; Lampert, E; Fortin, D; Veksler, V; Bigard, X; Mettauer, BOBJECTIVES: 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