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.

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    • "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]. "
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    • "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]. "
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