Increased entropy production in diaphragm muscle of PPARα knockout mice

Service de Physiologie, Hôpital de Bicêtre, Assistance Publique-Hôpitaux de Paris, Université Paris 11, Le Kremlin-Bicêtre, France. <>
Journal of Theoretical Biology (Impact Factor: 2.12). 02/2008; 250(1):92-102. DOI: 10.1016/j.jtbi.2007.09.022
Source: PubMed


Peroxisome proliferator activated receptor alpha (PPAR alpha) regulates fatty acid beta-oxidation (FAO) and plays a central role in the metabolic and energetic homeostasis of striated muscles. The thermodynamic consequences of the absence of PPAR alpha were investigated in diaphragm muscle of PPAR alpha knockout mice (KO). Statistical mechanics provides a powerful tool for determining entropy production, which quantifies irreversible chemical processes generated by myosin molecular motors and which is the product of thermodynamic force A/T (chemical affinity A and temperature T) and thermodynamic flow (myosin crossbridge (CB) cycle velocity upsilon). The behavior of both wild type (WT) and KO diaphragm was shown to be near-equilibrium and in a stationary state, but KO was farther from equilibrium than WT. In KO diaphragm, a substantial decrease in contractile function was associated with an increase in both A/T and upsilon and with profound histological injuries such as contraction band necrosis. There were no changes in PPAR delta and gamma expression levels or myosin heavy chain (MHC) patterns. In KO diaphragm, a marked increase in entropy production (A/T x upsilon) accounted for major thermodynamic dysfunction and a dramatic increase in irreversible chemical processes during the myosin CB cycle.

Download full-text


Available from: Pascal GP Martin
  • Source
    • "Finally, the heart is an open system that exchanges matter and energy with its environment and may operate either near equilibrium or, when myosin crossbridge kinetics become nonlinear in nature [18], far from equilibrium. The lack of PPARα in the PPARα −/− mouse model increases the distance from equilibrium in skeletal and cardiac muscles [19]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Peroxisome proliferator-activated receptors (PPAR alpha, beta/delta and gamma) play a key role in metabolic regulatory processes and gene regulation of cellular metabolism, particularly in the cardiovascular system. Moreover, PPARs have various extra metabolic roles, in circadian rhythms, inflammation and oxidative stress. In this review, we focus mainly on the effects of PPARs on some thermodynamic processes, which can behave either near equilibrium, or far-from-equilibrium. New functions of PPARs are reported in the arrhythmogenic right ventricular cardiomyopathy, a human genetic heart disease. It is now possible to link the genetic desmosomal abnormalitiy to the presence of fat in the right ventricle, partly due to an overexpression of PPARgamma. Moreover, PPARs are directly or indirectly involved in cellular oscillatory processes such as the Wnt-b-catenin pathway, circadian rhythms of arterial blood pressure and cardiac frequency and glycolysis metabolic pathway. Dysfunction of clock genes and PPARgamma may lead to hyperphagia, obesity, metabolic syndrome, myocardial infarction and sudden cardiac death, In pathological conditions, regulatory processes of the cardiovascular system may bifurcate towards new states, such as those encountered in hypertension, type 2 diabetes, and heart failure. Numerous of these oscillatory mechanisms, organized in time and space, behave far from equilibrium and are "dissipative structures".
    Full-text · Article · Jul 2010 · PPAR Research
  • Source
    • "PPARs belong to a family of nuclear receptors that regulate fatty acid metabolism via ligand-dependent transcriptional activation of target genes. PPARα mediates lipid-induced activation of fatty acid β-oxidation and plays a central role in the metabolic and energetic homeostasis of striated muscles in which it is abundantly expressed, including the diaphragm [34]. In PPARα knockout mice, diaphragmatic muscle mechanics, energetics, and cross-bridge kinetics are markedly impaired, leading to histological injuries [34]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Diabetes mellitus is associated with alterations in peripheral striated muscles and cardiomyopathy. We examined diaphragmatic function and fiber composition and identified the role of peroxisome proliferator-activated receptors (PPAR alpha and beta/delta) as a factor involved in diaphragm muscle plasticity in response to type I diabetes. Streptozotocin-treated rats were studied after 8 weeks and compared with their controls. Diaphragmatic strips were stimulated in vitro and mechanical and energetic variables were measured, cross bridge kinetics assessed, and the effects of fatigue and hypoxia evaluated. Morphometry, myosin heavy chain isoforms, PPAR alpha and beta/delta gene and protein expression were also assessed. Diabetes induced a decrease in maximum velocity of shortening (-14%, P<0.05) associated with a decrease in myosin ATPase activity (-49%, P<0.05), and an increase in force (+20%, P<0.05) associated with an increase in the number of cross bridges (+14%, P<0.05). These modifications were in agreement with a shift towards slow myosin heavy chain fibers and were associated with an upregulation of PPARbeta/delta (+314% increase in gene and +190% increase in protein expression, P<0.05). In addition, greater resistances to fatigue and hypoxia were observed in diabetic rats. Type I diabetes induced complex mechanical and energetic changes in the rat diaphragm and was associated with an up-regulation of PPARbeta/delta that could improve resistance to fatigue and hypoxia and favour the shift towards slow myosin heavy chain isoforms.
    Full-text · Article · Jul 2010 · PLoS ONE
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: EEG stimulus-related responses have been extensively studied to gain insight on the functional behavior of the brain. Traditionally, these responses have been considered as the result of the generation of low-amplitude evoked potentials (EP). When averaged, these low-amplitude potentials come up from the background and can be cleanly observed. Independent component analysis (ICA) is a technique widely used to solve the problem of blind source separation (BSS). When applied to EP, ICA provides a method to obtain activation signals of neural structures responsible for the generation of several components of EP. ICA algorithms may be modified in order to impose some constraints on the independent components (IC) to be extracted or the mixing matrix, resulting in the so-called constrained ICA (cICA). Here, we make use of a cICA approach to get those IC of the EP that can be identified with point-dipolar sources, as well as their position.
    Full-text · Conference Paper · Oct 2003
Show more