(Circulation. 2000;102:1847.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Heart Failure Affects Mitochondrial but Not Myofibrillar Intrinsic Properties of Skeletal Muscle
From the Cardiologie Cellulaire et Moléculaire U-446 INSERM (E. De S., V.V., P.M., R.V.-C.), Faculté de Pharmacie, Université Paris-Sud, Châtenay-Malabry, France; and Unité de Bioénergétique (X.B.), CRSSA, La Tronche Cedex, France.
Correspondence to Elvira De Sousa, U-446 INSERM, Faculté de Pharmacie, 92 296 Châtenay-Malabry, France. E-mail Elvira.desousa{at}cep.u-psud.fr
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Abstract |
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Background—Congestive heart failure (CHF) induces abnormalities in skeletal muscle that are thought to in part explain exercise intolerance. The aim of the present study was to determine whether these changes actually result in contractile or metabolic functional alterations and whether they are muscle type specific.
Methods and Results—With a rat model of CHF (induced by aortic banding), we studied mitochondrial function, mechanical properties, and creatine kinase (CK) compartmentation in situ in permeabilized fibers from soleus (SOL), an oxidative slow-twitch muscle, and white gastrocnemius (GAS), a glycolytic fast-twitch muscle. Animals were studied 7 months after surgery, and CHF was documented on the basis of anatomic data. Alterations in skeletal muscle phenotype were documented with an increased proportion of fast-type fiber and fast myosin heavy chain, decreased capillary-to-fiber ratio, and decreased citrate synthase activity. Despite a slow-to-fast phenotype transition in SOL, no change was observed in contractile capacity or calcium sensitivity. However, muscles from CHF rats exhibited a dramatic decrease in oxidative capacities (oxygen consumption per gram of fiber dry weight) of 35% for SOL and 45% for GAS (P<0.001). Moreover, the regulation of respiration with ADP and mitochondrial CK and adenylate kinase was impaired in CHF SOL. Mitochondrial CK activity and content (Western blots) were dramatically decreased in both muscles.
Conclusions—CHF results in alterations in both mitochondrial function and phosphotransfer systems but unchanged myofibrillar function in skeletal muscles, which suggests a myopathy of metabolic origin in CHF.
Key Words: heart failure • muscle • metabolism • mitochondria • creatine kinase
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Introduction |
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Muscular fatigue and reduced exercise tolerance are major symptoms of congestive heart failure (CHF). It is well accepted that central hemodynamics correlate poorly with exercise capacity in CHF. Attention has therefore been focused on peripheral factors such as alterations in skeletal muscle perfusion and intrinsic skeletal muscle abnormalities. Indeed, numerous studies in patients1 2 3 4 5 and animal models of heart failure6 7 8 9 10 11 have described muscle histological abnormalities, including fiber atrophy, fiber-type transformation toward more fast phenotype, and reduced oxidative enzyme activity. However, whether these abnormalities result in functional alterations of either the contractile machinery or sites of energy production has never been directly assessed.
31P NMR spectroscopy has revealed increased phosphocreatine (PCr) depletion and decreased intracellular pH during exercise in humans.12 PCr and creatine kinase (CK) are involved in the fine regulation between energy production and energy utilization in muscle cells. Generalized quantitative and functional alterations of the CK system are a hallmark of failing myocardium that contributes to alterations in intracellular energy fluxes and calcium homeostasis.13 14 Recently, a decreased content of mitochondrial CK (mi-CK) was observed in skeletal muscle of patients with CHF,15 although the CK function has never been assessed in skeletal muscle during CHF. Moreover, skeletal muscle in humans is composed of a mixture of fibers from fast glycolytic to slow oxidative, including intermediary fibers. Another important question, therefore, concerns the possible fiber or muscle type specificity of CHF-induced abnormalities.
The goal of the present study was therefore, with an animal model of prolonged chronic heart failure, to examine whether the morphological and biochemical changes observed in skeletal muscle will result in intrinsic contractile or metabolic alterations. Selective permeabilization of cellular membranes with detergents offers the unique opportunity to study in situ the myofibrillar and mitochondrial intrinsic properties, as well as CK compartmentation.16 We chose to examine the soleus (SOL), an oxidative slow-twitch muscle type, and the white gastrocnemius (GAS), a glycolytic fast-twitch muscle type, to also determine whether functional and biochemical changes might be fiber type specific.
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Methods |
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Rat Model of CHF
Weaned male Wistar rats (60 to 70 g) were randomly assigned to 1 of 2 groups. Aortic stenosis was created by placing a stainless steel hemoclip of 0.6-mm internal diameter on the ascending aorta via a thoracic incision (CHF group) according to Feldman et al17 as previously described.14 Age-matched control animals underwent the same procedure without placement of the clip (sham group). This investigation was carried out in accordance with the Helsinki Recommendations for Humane Treatment of Animals During Experimentation.
At 7 months after surgery, 7 CHF and 7 sham animals were anesthetized with an intraperitoneal injection of urethane (0.2 g/100 g), and the right and left SOL and superficial portions of GAS were isolated. A portion of the muscles were rapidly frozen for biochemical determinations.
Functional Properties of Mitochondria and Bound CK and
Adenylate Kinase
Respiratory parameters of the total mitochondrial
population were studied in situ in fresh saponin-skinned fibers as
previously described14 and determined with a Clark
electrode (Strathkelvin Instruments) in an oxygraphic cell containing 3
mL respiration solution (see later) at 22°C with continuous stirring.
Respiration rates were expressed as µmol
O2 · min-1 ·
g dry wt-1. Respiration solution was calculated
with the computer program of Fabiato18 and
contained (in mmol/L) EGTA-CaEGTA buffer 10 (free
Ca2+ concentration 100 nmol/L),
MgCl2 1, taurine 20, dithiothreitol 0.5,
imidazole 20 (pH 7.1), ionic strength 160 (potassium methane
sulfonate), glutamate 5, malate 2, and phosphate 3 and 2 mg/mL fatty
acid–free BSA. The ADP-stimulated respiration
(VADP) above basal oxygen consumption
(V0) was plotted as a function of [ADP] with or
without CK (20 mmol/L). The apparent
Km values for ADP and
VADP were calculated with nonlinear fit of
the Michaelis-Menten equation. The maximal respiration rate
(Vmax) was
(VADP+V0). The
acceptor control ratio (ACR) was
Vmax/V0. The
functional activity of adenylate kinase (AK) was evaluated in
the presence of 0.2 mmol/L ATP on the basis of the percent
increase in the respiration rate after the addition of 2 mmol/L
AMP (VAMP%). From 1 to 3 determinations
were made for each animal.
Mechanical Experiments
Muscle fiber bundles were dissected from SOL and GAS muscles in
a zero-Ca2+ Krebs’ solution (pH 7.4) and
permeabilized with 1% Triton X-100 in a relaxing
solution. Bundles were mounted between a vibrator and a force
transducer (model AE 801; SensoNor Microelectroniks) as previously
described.19 Sarcomere length was measured with laser
diffraction and adjusted to 2.5 to 2.6 µm. Solutions were
calculated with the computer program of Fabiato18 and
contained (in mmol/L) EGTA 10 (pCa 9 to 4.5), imidazole 30 (pH
7.1), Na+ 30.6, Mg2+ 3.16,
dithiothreitol 0.3, MgATP 3.16, PCr 12, and ionic strength 160
(potassium acetate). Data for each bundle were fit with nonlinear fit
of the Hill equation:
T=Ln/(K+Ln), where L is
the calcium concentration, T is the relative tension, K is a
constant, and n is the Hill coefficient.
Biochemical Studies
Frozen tissue samples were weighed and homogenized
in ice-cold buffer (50 mg/mL) containing (in mmol/L) HEPES 5 (pH
8.7), EGTA 1, dithiothreitol 1, and MgCl2 5 and
0.1% Triton X-100 and incubated for 60 minutes at 0°C to ensure
complete enzyme extraction. Enzyme activities were determined at
30°C, pH 7.5, as previously described with coupled enzyme
systems.14 CK and LDH isoenzymes were separated with
agarose (1%) gel electrophoresis performed at 200 V for 90 minutes and
revealed through incubation of the gels with a coupled enzyme system
(CK) or commercial revelation system (LDH reagent kit; Sigma Chemical
Co).
Myosin Determination
Native myosin was extracted as previously
described.19 Myosin heavy chain (MHC) isoforms were
separated with PAGE (90 V, 22 hours, 3°C). Immunohistochemical
studies were carried out on the midbelly portion of SOL and GAS. Serial
transverse sections (10 µm thick) were cut out at -20°C on a
cryostat and incubated for 1 hour at 37°C with specific antibodies
raised against (1) slow-type I (Novocastra, reference NCL-MHCS), (2)
all adult fast and developmentally regulated epitopes but not slow
myosin (MY-32; Sigma Chemical Co), (3) fast-type IIa (SC-71), (4) slow-
and fast-type IIa and type IIb but not type IIx MHC (BF-35), (5) or
fast-type IIb MHC isoforms (BF-F3). The avidin-biotin
immunohistochemical procedure was used for localization of the
antigen-antibody binding (Vector Laboratories). A sample of 
400
fibers was randomly selected and classified according to the staining
profile with a microscope linked to a computer-based image
analysis system (Visiolab 200; Nikon-France). Negative control
slides with omission of the primary antibodies were randomly included
in the immunostaining procedures.
Western Blot Analysis
Mouse mi-CK antibody (kind gift of Drs Z. Khuchua and W. Qin,
Washington University, St Louis, Mo) was produced in rabbit against
mouse whole recombinant sarcomeric mi-CK.20 Specificity of
the antibody and Western blot analyses were performed as
previously described.14 Briefly, 1.25 SOL and 5 GAS µg
protein extracts were separated, subsequently transferred to Hybond
nitrocellulose membranes (Amersham), and incubated with mi-CK antibody
for 2 hours. Membranes were revealed with ECL+ chemiluminescent
substrate (Amersham). Light emission was detected with
autoradiography, quantified with an image
analysis system (Bio-Rad), and normalized to SOL extract from
sham group.
Capillary Staining
Capillaries were visualized with an acidic ATPase reaction after
preincubation at pH 421 and identified with a microscope
linked to a computer-based image analysis system (Visiolab 200;
Nikon-France). From 4 to 6 areas were selected on each sample (total
area A). The capillary bed was appraised by (1) the capillary density,
calculated as the number of capillaries in A divided by the area of A,
and (2) the capillary-to-fiber ratio, determined as capillary density
normalized by the mean number of fibers/mm2.
Statistical Analysis
All data are expressed as mean±SEM. Data were statistically
evaluated with a Student’s t test between sham and CHF. A
2-way ANOVA, followed by Newman-Keuls post hoc test when appropriate,
was used to assess the main effects of muscle type (SOL versus GAS) and
condition (sham versus CHF). Values of P<0.05 were
considered significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Anatomic Data
CHF animals showed decreased body weight but normal skeletal growth on the basis of a similar tibia length (Table 1
). Increased absolute and relative
weights of the heart, both left and right ventricles, and the
lung in the CHF group indicated severe heart failure. Anatomic evidence
of cardiac decompensation (ascites, congestion, pleural effusion, and
edema), as well as our previous hemodynamic data (eg,
increased left ventricular end-diastolic
pressure from 10±4 to 62±18 mm Hg; see De Sousa et
al14 for details), confirmed the occurrence of severe CHF
in this model.
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Morphological and Mechanical Studies
CHF induced a significant absolute and relative decrease in SOL
weight (Table 2). The proportion of
fibers that expressed the slow MHC in CHF SOL decreased by 10%,
whereas that of fibers that expressed fast MHC exhibited a 6-fold
increase, only due to an increase in IIa MHC expression. Fast IIb MHC
was not detectable in CHF SOL. The proportion of slow MHC isoforms
decreased and fast MHC-IIa increased in CHF SOL (Table 2). The
appearance of IIx MHC in CHF SOL was not significant. GAS exhibited
exclusively fast IIx and IIb MHC isoforms. No significant changes were
observed in CHF.
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The number of capillaries per fiber and capillary density were higher in SOL than GAS muscle. In both CHF skeletal muscles, the number of capillaries per fiber was decreased, but capillary density remained unchanged.
Myofibrillar function was studied in Triton X-100–treated fiber
bundles to assess whether changes in contractile pattern will result in
alteration in the whole muscle function. Active tension was plotted as
a function of pCa in SOL (Figure 1A) and
GAS (Figure 1B) from control and CHF rats. Resting and active
tensions were significantly higher in GAS than in SOL, as well as slope
coefficient (nH), whereas calcium
sensitivity (pCa50) was lower (Table 3). None of these mechanical
parameters were altered in the CHF group.
|
, 
) and CHF (
, 
) rats are shown. Data
for each bundle were fitted with a nonlinear fit of the Hill equation
in sham (solid lines) and CHF (dotted lines) rats.
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Biochemical Data
The activity of AK, a phosphotransfer enzyme, higher in GAS than
SOL, was unchanged in both CHF muscles (Table 4). Compared with SOL, GAS exhibited a
clear glycolytic profile as shown by higher total LDH, PK, and
phosphoglycerate kinase (PGK) activities; lower activity
of CS; and absence of the aerobic subunit (H subunit) of LDH.
Activities of PK and PGK, the 2 steps of glycolytically produced ATP,
were maintained in both CHF muscles. Total LDH activity was not
changed in CHF muscles, but the ratio of H/M isoforms decreased in CHF
SOL. CS activity was depressed in both muscles.
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CK System
Both skeletal muscles expressed MM-CK and mi-CK isoenzymes only
(Table 5). GAS showed a typical fast
glycolytic profile as indicated by higher total and MM-CK activities
and lower content and activity of mi-CK. Total CK and MM-CK activities
were unchanged in CHF GAS but decreased in CHF SOL. The activity of
mi-CK decreased dramatically by 45% in SOL and 83% in GAS. The
mi-CK–to–citrate synthase ratio was similarly decreased. Western blot
analysis showed that this decrease could be accounted for by a
34% and 45% decrease in mi-CK protein content in CHF SOL and GAS,
respectively.
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Mitochondrial Function and CK
Oxygen consumption of permeabilized
preparations from sham and CHF rats was recorded as a function of
ADP concentration with or without creatine (Figure 2). Respiration rates were lower in GAS
than in SOL, whereas the ACRs were comparable (Table 6). In CHF rats, oxidative capacities
decreased by 35% and 45% in SOL and GAS, respectively. Because
the ACRs were high and preserved in CHF, this decrease suggested a
decreased amount of mitochondria without changes in the
oxidation-phosphorylation coupling. SOL was
characterized by a low sensitivity of respiration for
extramitochondrial ADP and a decreased apparent
Km value for ADP in the presence of
creatine, whereas for GAS, the apparent Km
value for ADP was very low and unchanged by the addition of creatine.
In the absence of creatine, the Km value
for ADP was significantly lower in CHF SOL and unchanged in CHF GAS.
The addition of creatine decreased the Km
value for ADP to a higher extent in CHF SOL than in control. The
stimulation of respiration by AMP in the presence of ATP was 40% in
control and only 22% in CHF SOL (P<0.01), showing an
impairment of mitochondrial AK efficacy.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Major Findings
The present study shows that the changes in contractile phenotype of skeletal muscles observed in CHF do not result in alterations in intrinsic mechanical properties of myofilaments. On the contrary, mitochondrial respiration and energy transfer systems (CK) are quantitatively and qualitatively altered in CHF muscles. These alterations are more relevant to a metabolic myopathy in heart failure than a simple phenoconversion. The fact that mitochondria of both fast glycolytic and slow oxidative muscles are affected suggests that a central mechanism might be involved.
Contractile Function
This experimental model of heart failure has been well
characterized14 17 and reproduced the main skeletal muscle
abnormalities previously described in animal studies or in patients
with CHF.2 3 5 7 9 11 22 We report here a reduced number
of capillaries and changes in MHC expression in SOL from CHF rats that
consist of decreased type I MHC expression and increased fast-type IIa
MHC expression. Fibers generally express a whole set of contractile
proteins of a specific type, including regulatory proteins of the thin
filament. This results in different intrinsic mechanical properties
such as a higher calcium sensitivity and lower Hill coefficient in slow
versus fast fibers (for a review, see Schiaffino and
Reggiani23 ). Despite changes in myosin expression and
decreased expression of skeletal actin,10 skinned fibers
of SOL muscle of CHF rats exhibited mechanical properties identical to
those of control fibers. Although nothing is known concerning possible
changes in troponin isoform expression in skeletal muscle in CHF, these
changes are not important enough to modify contractile capacity and
sensitivity to calcium.
Metabolism and CK System
Skeletal muscle phenotype is also characterized by the
type of energy metabolism adapted to function. Fast fibers
have a predominantly glycolytic metabolism, whereas slow
fibers are mainly oxidative. In either muscle type, CHF did not result
in altered glycolytic enzyme activity, which is in agreement with
studies in animals or patients.1 2 6 11 It should be
mentioned that the slight decrease in LDH isoenzyme ratio nevertheless
suggests an increase in anaerobic metabolism in
CHF SOL. Energy transfer systems are important in the adjustment of
energy production to demand. CK fulfills specific roles in
glycolytic and oxidative muscles.24 25 Fast glycolytic
muscles have a high activity of both total and the cytosolic isoform of
CK (MM-CK) as correlated to the speed of contraction,26
whereas slow oxidative muscles exhibit a lower total activity of CK and
a higher amount of mi-CK, which provides an efficient system of energy
transfer from mitochondria to ATPases. This study shows that the CK
system is clearly altered in skeletal muscle from rats with severe CHF.
However, as a result of a slow-to-fast shift in fiber type in SOL, an
increase in MM-CK was expected rather than a decrease.19
This decrease in MM-CK is reminiscent of what is observed in the
failing myocardium of humans and animals13 14
and seems to be specific to heart failure. In addition, a drop in mi-CK
that exceeds the decrease in mitochondrial mass was observed in both
muscle types, extending the observations made by Hambrecht et
al15 in patients. Mi-CK decrease could thus be proposed as
a generalized marker of the severity of metabolic
alterations in myocardium and skeletal muscles of patients
with CHF (see Nascimben et al13 and De Sousa et
al14 and references therein).
Mitochondrial Function
Early PCr depletion, decreased intracellular pH, increased lactate
production at exercise, and alterations in mitochondrial volume
density and enzyme activities1 2 3 4 6 8 9 10 11 12 have supported
the proposal that oxidative skeletal muscle metabolism is
impaired in CHF, although decreased mitochondrial enzyme activities are
not always reported and could be enzyme or muscle
dependent.1 11 22 These results provide the first
functional evidence for a marked fall in oxidative capacity, affecting
both oxidative and glycolytic muscles.
Moreover, we could observe qualitative changes in mitochondrial respiration specifically in oxidative muscle. CHF resulted in a decrease in the control of respiration by mitochondrial kinases (AK and CK). Mitochondrial respiration in oxidative muscles is preferentially regulated by intramitochondrially produced ADP through phosphokinases, whereas such fine control is absent in glycolytic muscle.16 24 This regulation provides a specialized system through which a cytosolic metabolic pathway is linked to mitochondrial respiration.27 Whether this increase in ADP sensitivity could be a compensatory mechanism for the drop in mi-CK activity and content to preserve mitochondrial function is at present only speculative.
Clinical Implications
The general conclusion of the present study is that heart
failure markedly affected the mitochondrial capacity and regulation
rather than intrinsic contractile machinery of skeletal muscles. Many
studies, including the close relation between peak
O2 and mitochondrial enzyme
activity or volume,3 4 28 have pointed out that impaired
aerobic metabolism may play a role in the limitation of
systemic exercise capacity. The decreased oxidative capacity and
altered mitochondrial regulation and energy transfer demonstrated here
could be the mechanistic basis for decreased oxygen utilization and
exercise capacity in CHF. Because skeletal muscle abnormalities have
some similarities with deconditioning, reduced physical activity of
patients with CHF has been proposed as a possible cause of these
alterations.1 3 However, several observations have raised
the possibility of a specific myopathy in this pathology. In some
cases, a decrease in (or even disappearance of) type I MHC expression
may far exceed changes attributable to exercise
deconditioning.5 Considering animal models of heart
failure, reduced activity cannot explain skeletal muscle
abnormalities.9 Moreover, in a model of severe muscle
deconditioning induced by hindlimb suspension, oxidative
metabolism and mitochondrial properties were preserved in
contrast to what is observed in heart failure.19 This
argues the case for a specific metabolic myopathy in heart
failure.
The fact that decreased oxidative capacity and altered mitochondrial regulation can be encountered in cardiac slow-oxidative and fast-glycolytic muscles suggests that central mechanism or systemic factors are involved. Alterations in the neurohumoral system or circulating factors such as cytokines and tissue necrosis factor can affect skeletal muscle. Recently, a negative correlation was found among the expression of mi-CK in skeletal muscle, exercise capacity, and the expression of inducible NO synthase, suggesting that inducible NO synthase may be involved in exercise intolerance of patients with CHF.15
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Acknowledgments |
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Dr Ventura-Clapier is supported by Centre National de la Recherche Scientifique. This work was supported by a PROGRES grant from INSERM and a grant from Association Française contre les Myopathies.
Received February 11, 2000; revision received April 26, 2000; accepted May 9, 2000.
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 R. Ventura-Clapier, A. Garnier, and V. Veksler Energy metabolism in heart failure J. Physiol., February 15, 2004; 555(1): 1 - 13. [Abstract] [Full Text] [PDF]
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 L. Dalla Libera, B. Ravara, M. Volterrani, V. Gobbo, M. Della Barbera, A. Angelini, D. D. Betto, E. Germinario, and G. Vescovo Beneficial effects of GH/IGF-1 on skeletal muscle atrophy and function in experimental heart failure Am J Physiol Cell Physiol, January 1, 2004; 286(1): C138 - C144. [Abstract] [Full Text] [PDF]
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W. H. Lee, J. S. Gounarides, E. S. Roos, and M. S. Wolin Influence of peroxynitrite on energy metabolism and cardiac function in a rat ischemia-reperfusion model Am J Physiol Heart Circ Physiol, October 1, 2003; 285(4): H1385 - H1395. [Abstract] [Full Text] [PDF]
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A Garnier, D Fortin, C Delomenie, I Momken, V Veksler, and R Ventura-Clapier Depressed mitochondrial transcription factors and oxidative capacity in rat failing cardiac and skeletal muscles J. Physiol., September 1, 2003; 551(2): 491 - 501. [Abstract] [Full Text] [PDF]
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 R. Persinger, Y. Janssen-Heininger, S. S. Wing, D. E. Matthews, M. M. LeWinter, and M. J. Toth Effect of heart failure on the regulation of skeletal muscle protein synthesis, breakdown, and apoptosis Am J Physiol Endocrinol Metab, May 1, 2003; 284(5): E1001 - E1008. [Abstract] [Full Text] [PDF]
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 F. Ribera, B. N'Guessan, J. Zoll, D. Fortin, B. Serrurier, B. Mettauer, X. Bigard, R. Ventura-Clapier, and E. Lampert Mitochondrial Electron Transport Chain Function Is Enhanced in Inspiratory Muscles of Patients with Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., March 15, 2003; 167(6): 873 - 879. [Abstract] [Full Text] [PDF]
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E. De Sousa, P. Lechene, D. Fortin, B. N'Guessan, S. Belmadani, X. Bigard, V. Veksler, and R. Ventura-Clapier Cardiac and skeletal muscle energy metabolism in heart failure: beneficial effects of voluntary activity Cardiovasc Res, November 1, 2002; 56(2): 260 - 268. [Abstract] [Full Text] [PDF]
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 R. Ventura-Clapier, E. De Sousa, and V. Veksler Metabolic Myopathy in Heart Failure Physiology, October 1, 2002; 17(5): 191 - 196. [Abstract] [Full Text] [PDF]
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 R. Hambrecht, P. C. Schulze, S. Gielen, A. Linke, S. Mobius-Winkler, J. Yu, J.u. Kratzsch, G. Baldauf, M. W. Busse, A. Schubert, et al. Reduction of insulin-like growth factor-I expression in the skeletal muscle of noncachectic patients with chronic heart failure J. Am. Coll. Cardiol., April 3, 2002; 39(7): 1175 - 1181. [Abstract] [Full Text] [PDF]
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B. Mettauer, J. Zoll, H. Sanchez, E. Lampert, F. Ribera, V. Veksler, X. Bigard, P. Mateo, E. Epailly, J. Lonsdorfer, et al. Oxidative capacity of skeletal muscle in heart failure patients versus sedentary or active control subjects J. Am. Coll. Cardiol., October 1, 2001; 38(4): 947 - 954. [Abstract] [Full Text] [PDF]
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H. Tsutsui, T. Ide, S. Hayashidani, N. Suematsu, T. Shiomi, J. Wen, K.-i. Nakamura, K. Ichikawa, H. Utsumi, and A. Takeshita Enhanced Generation of Reactive Oxygen Species in the Limb Skeletal Muscles From a Murine Infarct Model of Heart Failure Circulation, July 10, 2001; 104(2): 134 - 136. [Abstract] [Full Text] [PDF]
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