PPARβ/δ activation key to ‘marathon mice’
MedWire News: Nuclear receptors are involved in regulating glucose metabolism by muscles, in a manner that resembles the effects of exercise training, say US researchers.
Writing in the journal Genes and Development, they say that the peroxisome proliferator-activated receptor (PPAR) β/δ is able to boost muscle glucose utilization, and that mice engineered to express this receptor are superfit "marathon mice."
"Essentially, these transgenic mice are capable of storing and burning sugars at rates usually only seen in the trained athlete. This allows for supranormal athletic performance," said Daniel Kelly (Sanford-Burnham Medical Research Institute, Orlando, Florida), the study's lead author, in a press release.
Kelly's team investigated the regulatory pathways involved in controlling skeletal muscle energy metabolism. They developed mouse models that expressed either muscle-specific PPARβ/δ (which are known to have enhanced exercise performance) or muscle-specific PPARα (which perform at low levels).
The mice underwent exercise studies using a motorized treadmill. Compared with nontransgenic littermates, PPARβ/δ mice ran longer distances and at a faster pace whereas PPARα mice ran shorter distances.
Mice were then euthanized and their muscle tissue analysed. Interestingly, PPARβ/δ mice produced lower amounts of lactic acid, despite their superior athletic performance. This is important because lactic acid is considered the chief mediator of exercise-induced muscle pain, say the researchers.
Molecular analysis revealed that expression ratio of the lactate dehydrogenase b (Ldhb) and Ldha genes was increased in PPARβ/δ mice. This isoenzyme shift would divert pyruvate into the mitochondrion for the final steps of glucose oxidation, Kelly et al explain.
Further studies showed that PPARβ/δ but not PPARα interacted with the exercise-inducible kinase AMP-activated protein kinase to activate Ldhb gene transcription. This was a synergistic pathway that interacted with myocyte enhancer factor 2A in a PPARβ/δ-ligand-independent manner.
Finally, muscle from PPARβ/δ mice was found to have high glycogen stores, increased levels of glucose transporter type 4, and augmented capacity for mitochondrial pyruvate oxidation, "suggesting a broad reprogramming of glucose utilization pathways."
Commenting on their findings, Kelly said: "Given the association of obesity and insulin resistance with diets enriched in simple sugars, we find these results promising as a step towards new therapeutics.
"Previously, members of the PPAR protein family have proven to be difficult drug targets due to the wide variety of effects they have in a cell. However, the findings in this study suggest that strategies for activating only a subset of events downstream of PPARβ/δ are possible. This could lead to favorable metabolic effects on muscle and other tissues."
By Joanna Lyford