Increased entropy production in diaphragm muscle of PPAR α knockout mice

Peroxisome proliferator activated receptor alpha (PPAR α) regulates fatty acid β-oxidation (FAO) and plays a central role in the metabolic and energetic homeostasis of striated muscles. The thermodynamic consequences of the absence of PPAR α were investigated in diaphragm muscle of PPAR α 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 υ). 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 υ and with profound histological injuries such as contraction band necrosis. There were no changes in PPAR δ and γ expression levels or myosin heavy chain (MHC) patterns. In KO diaphragm, a marked increase in entropy production ( A/ T× υ) accounted for major thermodynamic dysfunction and a dramatic increase in irreversible chemical processes during the myosin CB cycle.