Oxidative capacity of skeletal muscle in heart failure patients versus sedentary or active control subjects
Bertrand Mettauer, MD, PhD*,
Joffrey Zoll, BS*,
Hervé Sanchez, BS*,
Eliane Lampert, MD*,
Florence Ribera, BS*,
Vladimir Veksler, MD, PhD ,
Xavier Bigard, MD, PhD ,
Philippe Mateo, PhD,
Eric Epailly, MD*,
Jean Lonsdorfer, MD* and
Renée Ventura-Clapier, PhD
* Département de Physiologie, Faculté de Médecine, Université Louis Pasteur, 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
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Figure 1 Examples of the Michaelis-Menten kinetics of the oxygen consumption of permeabilized vastus lateralis myofibers to increasing levels of the phosphate acceptor adenosine diphosphate (ADP). (A) Raw data obtained by myofibers respiration within the oxygraphic chamber from a representative patient with chronic heart failure (CHF) (upper) and an active control (lower). The tissue O2 consumption (V, µmoles O2·min–1·g–1 dry weight) increases with increasing doses of the phosphate acceptor ADP. These experiments were performed in the absence (thick line) or in the presence (thin line) of 20 mM creatine. Panel B shows the ADP-related respiration characterizing the Michaelis and Menten kinetics of ADP phosphorylation for the same CHF (interrupted lines) or active normal controls (ACT) (continuous line) groups as in panel A. The upper part represents the experiments without creatine and the lower part those with 20 mM creatine. The striking difference in maximal tissue oxygen uptake between the patients with CHF and the active control group is reflected by the differing asymptotic values of O2 uptake. In CHF, the fast increase in oxygen uptake with ADP reflects the low Km without creatine (42 µM), which is unchanged with creatine (25 µM). In the active control, the Km is much higher (214 µM) and decreases with creatine (59 µM).
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Figure 2 Comparison between exercise capacity and oxidative capacity of vastus lateralis muscle. The maximal adenosine diphosphate (ADP)-stimulated respiration rate of the saponin-skinned fibers (maximal tissue oxygen uptake [Vmax], µmol O2·min–1·g–1 dry weight tissue, left panel) were identical between patients with chronic heart failure (CHF) (open bars) and sedentary controls (SED) (hatched bars), both differing from active controls (ACT) (black bars). The peak oxygen uptake ([VO2 peak] ml·min–1·kg–1, middle panel) and the O2 uptake at the ventilatory threshold ([VO2 at VT] ml·min–1·kg–1, right panel), representing exercise capacity, highly differed among groups in the order CHF < SED < ACT.
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Figure 3 Apparent Michaelis-Menten constant without and with creatine for the adenosine diphosphate (ADP)-stimulated respiration of myofibers. The apparent Michaelis-Menten constant ([KmADP] µM) of the saponin-skinned fibers without creatine (hatched bars) were similarly low in patients with chronic heart failure (CHF) and sedentary controls (SED) and unchanged with the addition of creatine (black bars). In the active controls (ACT) the high Km value, which decreases with creatine, shows that the oxygen consumption is controlled by the mitochondrial creatine kinase.
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Figure 4 Correlation between exercise capacity and muscle oxidative capacity. (A) The relation between myofibers oxidative capacity and peak oxygen uptake (VO2 peak) (ml·min–1·kg–1) of patients with chronic heart failure (CHF) (open circles) is shifted leftward from the normal relation in controls (sedentary subjects: open triangles; active controls: closed triangles). (B) The relation between myofibers oxidative capacity and VO2 (ml·min–1·kg–1) at ventilatory threshold (VT), taken as an index of endurance capacity, of CHF patients is also shifted leftward from the normal relation in controls (symbols as in A).
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