Increased entropy production in diaphragm muscle of PPAR alpha 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: 2.3). 02/2008; 250(1):92-102. DOI: 10.1016/j.jtbi.2007.09.022
Source: PubMed

ABSTRACT 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, Aug 16, 2015
  • 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".
    PPAR Research 07/2010; 2010. DOI:10.1155/2010/783273 · 1.64 Impact Factor
  • 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.
    Engineering in Medicine and Biology Society, 2003. Proceedings of the 25th Annual International Conference of the IEEE; 10/2003
  • [Show abstract] [Hide abstract]
    ABSTRACT: Respiratory failure is a major cause of mortality during septic shock and is due in part to decreased ventilatory muscle contraction. Ventilatory muscles have high energy demands; fatty acid (FA) oxidation is an important source of ATP. FA oxidation is regulated by nuclear hormone receptors; studies have shown that the expression of these receptors is decreased in liver, heart, and kidney during sepsis. Here, we demonstrate that lipopolysaccharide (LPS) decreases FA oxidation and the expression of lipoprotein lipase (LPL), FA transport protein 1 (FATP-1), CD36, carnitine palmitoyltransferase beta, medium chain acyl-CoA dehydrogenase (MCAD), and acyl-CoA synthetase, key proteins required for FA uptake and oxidation, in the diaphragm. LPS also decreased mRNA levels of PPARalpha and beta/delta, RXRalpha, beta, and gamma, thyroid hormone receptor alpha and beta, and estrogen related receptor alpha (ERRalpha) and their coactivators PGC-1alpha, PGC-1beta, SRC1, SRC2, Lipin 1, and CBP. Zymosan resulted in similar changes in the diaphragm. Finally, in PPARalpha deficient mice, baseline CPT-1beta and FATP-1 levels were markedly decreased and were not further reduced by LPS suggesting that a decrease in the PPARalpha signaling pathway plays an important role in inducing some of these changes. The decrease in FA oxidation in the diaphragm may be detrimental, leading to decreased diaphragm contraction and an increased risk of respiratory failure during sepsis.
    The Journal of Lipid Research 06/2009; 50(10):2055-63. DOI:10.1194/jlr.M800655-JLR200 · 4.73 Impact Factor
Show more