Objective: 

The transcriptional coactivator PGC-1a is involved in the exercise-induced increase in muscular mitochondrial content. PGC-1a activity is regulated by various posttranslational modifications among them acetylation or phosphorylation. Accordingly, the deacetylase SIRT1 and the kinase AMPK have been shown to increase PGC-1a activity.

Research Design and Methods: 

We tested the hypothesis, whether physical activity (treadmill training, 12 weeks) modifies PGC-1a activation and mitochondrial biogenesis differentially in mildly obese IL-6-deficient mice and severely obese ob/ob mice with dysregulated AMPK activation compared to C57BL/6J wild-type mice with intact adiponectin/leptin-mediated AMPK activation.

Results: 

Physical activity induced adiponectin, lowered plasma insulin and glucose, suggesting improved insulin sensitivity, in wild-type and IL-6-deficient mice. It also enhanced mitochondrial biogenesis in these mice as indicated by increased expression of transcriptional regulators (PGC-1a, Tfam, NRF-1) and primary mitochondrial transcripts, increased mtDNA content and enhanced citrate synthase activity. Parallel to these changes, we observed AMPK activation, PGC-1a deacetylation and SIRT1 induction in the trained wild-type and IL-6-deficient mice. Although none of these training-induced changes were detected in ob/ob mice, comparable effects on mitochondrial respiration were observed.

Conclusions: 

Endurance training induces mitochondrial biogenesis in wild-type and IL-6-deficient mice, which may require intact AMPK activation and involve SIRT1-dependent PGC-1a deacetylation. Trained ob/ob mice show no signs of increased mitochondrial biogenesis but similar changes in mitochondrial respiration. Thus, ob/ob mice appear to have partially adapted to reduced mitochondrial biogenesis by AMPK/SIRT1/PGC-1a-independent mechanisms without mtDNA replication.