PPARgamma agonist pioglitazone does not enhance performance in mice

Abstract

Peroxisome-proliferator-activated receptor (PPAR) delta and adenosine monophosphate (AMP)-activated protein kinases (AMPKs) regulate the metabolic and contractile characteristics of myofibres. PPAR proteins are nuclear receptors that function as transcription factors and regulate the expression of multiple genes. AMPK has been described as a master metabolic regulator which also controls gene expression through the direct phosphorylation of some nuclear proteins. Since it was discovered that both PPARdelta agonists (GW1516) and AMPK activators (5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, known as AICAR) are very effective performance-enhancing substances in sedentary mice, the World Anti-doping Agency (WADA) included AICAR and GW1516 in the prohibited list of substances as metabolic modulators in the class 'Hormone and metabolic modulators'. Thiazolidinediones are PPARgamma agonists that can induce similar biological effects to those of PPARdelta and PPARdelta-AMPK agonists. Thus in this study, the effects of pioglitazone on mitochondrial biogenesis and performance were evaluated. Blood glucose levels and the protein expression of the intermediates involved in the mitochondrial biogenesis pathway and the citrate synthase activity were determined in both gastrocnemius and soleus muscles. Maximal aerobic velocity (MAV), endurance capacity, and grip strength before and after the training period were also determined. The MAV endurance capacity and grip strength of trained animals significantly increased. We found that the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and the nuclear respiratory factor-1 (NRF-1) protein content and citrate synthase activity significantly increased in the soleus muscle of trained animals. No effect of treatment was found. Therefore in our study, pioglitazone administration did not affect mitochondrial biogenesis signaling pathway.

Role of plakophilin-2 expression on exercise-related progression of arrhythmogenic right ventricular cardiomyopathy: a translational study

“…3 Experiments were approved under NYU-IACUC protocol IA16-01021. Mice underwent two separate treadmill running protocols adapted from [11][12][13] : (i) 3 weeks of running before first tamoxifen (TAM) injection and then three additional weeks of running (total 6 weeks of exercise; Supplementary material online,…”

The antidepressant-like effects of pioglitazone in a chronic mild stress mouse model are associated with PPARγ-mediated alteration of microglial activation phenotypes

“…CMS induced a decrease in locomotor activity indicated a depressive state of animals because of a loss of interest for the movement, or for exploring the environment. Pioglitazone increased spontaneous motor activity in the CMS-exposed mice, without effect on locomotor activity in normal mice [ 38 ]. Gavage administration of pioglitazone was effective at the 2.5 and 5.0 mg/kg doses for ameliorating the symptoms of depression, but the 2.5 mg/kg dosage was more effective.…”

Activation of AMPK and its Impact on Exercise Capacity

“…Pioglitazone, in contrast to training alone, did not enhance maximal aerobic velocity, endurance capacity, and grip strength. Furthermore, expression of mitochondrial biogenesis markers, such as PGC-1a and citrate synthase activity in the soleus muscle, were not changed after pioglitazone treatment of mice [75]. In contrast, a clinical study showed that rosiglitazone (4 mg daily for a period of 4 months) increased maximal exercise capacity in individuals with type 2 diabetes.…”