The highly efficient powerhouse in the Wistar audiogenic rat, an epileptic rat strain

Abstract

The Wistar audiogenic rat (WAR) is an animal model of tonic-clonic epileptic seizures, developed after genetic selection by sister × brother inbreeding of Wistar rats susceptible to sound stimuli. Although metabolic changes have been described in this strain, nothing is known about its mitochondrial metabolism. Here, we addressed mitochondrial aspects of oxidative phosphorylation, oxidative stress, biogenesis, and dynamics in liver, skeletal muscle, and heart of male WARs and correlating them with physiological aspects of body metabolism. The results showed higher mitochondrial content, respiration rates in phosphorylation and noncoupled states, and H2O2 production in WARs. Liver presented higher content of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α) and mammalian target of rapamycin, proteins related to mitochondrial biogenesis. In agreement, isolated liver mitochondria from WARs showed higher respiration rates in phosphorylation state and ADP-to-O ratio, as well as higher content of proteins related to electron transport chain ATP synthase, TCA cycle, and mitochondrial fusion and fission compared with their Wistar counterparts. Mitochondria with higher area and perimeter and more variable shapes were found in liver and soleus from WARs in addition to lower reduced-to-oxidized glutathione ratio. In vivo, WARs demonstrated lower body mass and energy expenditure but higher food and water intake and amino acid oxidation. When exposed to a running test, WARs reached higher speed and resisted for a longer time and distance than their Wistar controls. In conclusion, the WAR strain has mitochondrial changes in liver, skeletal muscle, and heart that improve its mitochondrial capacity of ATP production, making it an excellent rat model to study PGC1α overexpression and mitochondrial function in different physiological conditions or facing pathological challenges.

Energy Metabolism and Redox State in Brains of Wistar Audiogenic Rats, a Genetic Model of Epilepsy

“…In a previous study of our group, we found the same mitochondrial and oxidative profile in the liver, soleus muscle and cardiac tissue of WAR (60). In these organs, the changes were associated with higher expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) and mammalian target of rapamycin (mTOR).…”

Pre- and Post-Endurance Training Mitigates the Rat Pilocarpine-Induced Status Epilepticus and Epileptogenesis-Associated Deleterious Consequences

“…Epilepsy is a heterogeneous brain disorder affecting 1 to 3% of the population worldwide. The main symptom of epilepsy is the onset of spontaneous seizures resulting from an impaired excitatory/inhibitory balance [ 1 ]. Temporal lobe epilepsy (TLE) is the most frequent type of epilepsy, and the most refractory type to drug treatment [ 2 ].…”

“…Since clinical studies cannot provide sufficient information about the precise mechanisms underlying seizure susceptibility and epileptogenesis, animal models for epilepsy are a reliable approach for such mechanistic studies [ 1 ]. Pilocarpine (Pilo) is one of the most widely used convulsant agents that induce status epilepticus (SE), followed by neurochemical alterations and structural and functional changes similar to those observed in epileptic patients [ 15 ].…”