Oxidative capacity of skeletal muscle in heart failure patients versus sedentary or active control subjects

Mettauer, Bertrand; Zoll, Joffrey; Sanchez, Hervé; Lampert, Eliane; Ribera, Florence; Veksler, Vladimir; Bigard, Xavier; Matéo, Philippe; Epailly, Éric; Lonsdorfer, J.; Ventura‐Clapier, Renée

doi:10.1016/s0735-1097(01)01460-7

Cited by 113 publications

(136 citation statements)

References 33 publications

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“…Similarly, losartan, an Ang II type 1 receptor antagonist, was shown to partially reverse the MI-induced downregulation of PGC-1␣ expression in male rats 12 but not in female rats. 11 These partial cardiac and total "peripheral" beneficial effects of ACEi therapy on mitochondrial function and biogenesis could thus explain the different results observed in human failing skeletal 14,15 and cardiac muscle (present results). Understanding the events mediating the decreased oxidative capacity in failing heart seems to be of major significance.…”

Section: Angiotensin-converting Enzyme Inhibition and Mitochondrial Fmentioning

confidence: 47%

“…13 In contrast to experimental models, 4 in patients with severe CHF under angiotensin-converting enzyme inhibition (ACEi) therapy, skeletal muscle mitochondrial oxidative capacity and oxidative phosphorylation protein expression are preserved, despite lower exercise capacity. 14 In line with this maintained function, no evidence for deactivation of PGC-1␣ regulatory cascade was found, although, in healthy subjects, exercise performance is associated with improvement in mitochondrial function, PGC-1␣ activation, and increased expression of mitochondrial proteins. 15 This suggests a possible protective effect of ACEi on muscle energy metabolism.…”

Section: Editorial See P 275 Clinical Perspective On P 350mentioning

confidence: 78%

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Control by Circulating Factors of Mitochondrial Function and Transcription Cascade in Heart Failure

Garnier

Zoll

Fortin

et al. 2009

Circ: Heart Failure

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Background-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-␥ coactivator-1␣, 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-␥ coactivator-1␣ 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-␥ coactivator-1␣ 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 (Ϫ30%) and, to a lesser degree, angiotensin II (Ϫ20%) decreased proliferator-activated receptor-␥ coactivator-1␣ 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. (Circ Heart Fail. 2009;2:342-350.)

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Section: Angiotensin-converting Enzyme Inhibition and Mitochondrial Fmentioning

confidence: 47%

Section: Editorial See P 275 Clinical Perspective On P 350mentioning

confidence: 78%

Control by Circulating Factors of Mitochondrial Function and Transcription Cascade in Heart Failure

Garnier

Zoll

Fortin

et al. 2009

Circ: Heart Failure

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“…Significant reductions in the activity of citrate synthase (CS) [10][11][12] 30 . In contrast, the method of MAPR, used in the current study, is a direct and comprehensive assessment of muscle oxidative capacity across the entire range of metabolic energy producing pathways 19,31,32 .…”

Section: Discussionmentioning

confidence: 99%

Reduced exercise tolerance in CHF may be related to factors other than impaired skeletal muscle oxidative capacity

Williams¹,

Selig²,

Hare³

et al. 2004

Journal of Cardiac Failure

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“…The rationale is based on 2 observations: circulating hormones such as endothelin-1 (ET-1) are hyperactivated in heart failure patients 5 and, as shown in previous work by this group, ACEi treatment was found to correct mitochondrial defects in skeletal muscle of heart failure patients. 6 The specific hypotheses tested were (1) myocardial mitochondrial oxidative capacity is lower in ACEi-treated heart failure patients, (2) ACEi therapy protects myocardial mitochondrial function by activating PGC-1␣ expression, and (3) hormonal signals induce the PGC-1␣ transcription cascade. Three sets of experiments were performed.…”

Section: Article See P 342mentioning

confidence: 99%

On the Control of Metabolic Remodeling in Mitochondria of the Failing Heart

Ingwall

2009

Circ: Heart Failure

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T he metabolic phenotype of the failing heart may be defined as follows. 1 Metabolism remodels in the failing heart, leading to a loss in energy reserve and the inability to increase ATP supply. Ultimately, this metabolic rigidity leads to a fall in ATP. The likely time line is decreased energy reserve via the phosphotransferase reactions (creatine kinase [CK] and adenylate kinase) leading to increases in ADP and AMP, triggering an increase in glycolysis. Although the contribution of glycolysis to overall ATP synthesis increases at least in the hypertrophied heart, glycolytic reserve is limited. Importantly, as heart failure evolves, ATP synthesis from oxidation of both endogenous and exogenous fatty acids by mitochondria, the major source of ATP in the heart, falls. 2 Article see p 342Remodeling of the failing myocardium is controlled by energy sensors such as AMP that lead to changes in phosphorylation state (as well as other chemical modifications) of many proteins for short-term preservation of ATP and by activation of transcription factors that coordinately control long-term remodeling of entire ATP synthesis and utilizing pathways.Given that the requirement for ATP for all metabolic processes and for cell viability is absolute, a renewed interest in metabolism has led to identification of the molecular links between physiological and metabolic stimuli and the regulation of gene expression in the heart. We not only have identified the metabolic targets of specific nuclear receptors and DNA-binding transcriptional activators but also are beginning to learn how their signals are amplified and sustained to remodel metabolism.Transcription is activated when transcriptional activators, including peroxisome proliferator-activated receptors, estrogen receptors, retinoid receptors, nuclear respiratory factors, and myocyte-enhancing factor-2 (MEF-2) form proteinprotein complexes with the peroxisome proliferator-activated receptor-␥ coactivators, namely PGC-1␣ and ␤, tethering PGC-1s to DNA (Figure). When complexed with the transcription activators, PGC-1s activate genes encoding proteins comprising entire metabolic pathways that control ATP synthesis in mitochondria (fatty acid uptake, ␤-oxidation, oxidative phosphorylation, the Krebs cycle, and electron transport chain), phosphoryl transfer (sarcomeric mitochondrial CK and adenine nucleotide transporter), glucose uptake and utilization, and ATP-utilizing proteins (Figure). The different transcription factors confer specificity of PGC-1s for its genomic targets. Substantial overlap exists, and there is much to learn about the full range of targets. Because of its central role in transcriptional control of metabolism, PGC-1␣ is referred to as a master regulator.PGC-1␣ is itself regulated. For example, the cyclindependent kinases Cdk9 and Cdk7 target PGC-1␣, thereby conferring additional specificity for the transcriptional control of ATP synthesizing and utilizing reactions. Other known regulators of PGC-1␣ in striated muscle include p38 mitogenactivated protein kina...

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Oxidative capacity of skeletal muscle in heart failure patients versus sedentary or active control subjects

Abstract: In these patients, the disease-specific muscle metabolic impairments derive mostly from extramitochondrial mechanisms that disrupt the normal symmorphosis relations. The possible roles of ACE inhibitors and level of activity are discussed.

Cited by 113 publications

References 33 publications

Control by Circulating Factors of Mitochondrial Function and Transcription Cascade in Heart Failure

Control by Circulating Factors of Mitochondrial Function and Transcription Cascade in Heart Failure

Reduced exercise tolerance in CHF may be related to factors other than impaired skeletal muscle oxidative capacity

On the Control of Metabolic Remodeling in Mitochondria of the Failing Heart

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