Pknox1/Prep1 regulates mitochondrial oxidative phosphorylation components in skeletal muscle.
The homeodomain transcription factor Prep1 was previously shown to regulate insulin sensitivity. Our aim was to study the specific role of Prep1 for the regulation of energy metabolism in skeletal muscle. Muscle-specific ablation of Prep1 resulted in increased expression of respiratory chain subunits. This finding was consistent with an increase in mitochondrial enzyme activity without affecting mitochondrial volume fraction as assessed by electron microscopy. Metabolic phenotyping revealed no differences in daily energy expenditure or body composition. However, during treadmill exercise challenge, Prep1 ablation resulted in a higher maximal oxidative capacity and better endurance. Elevated PGC-1α expression was identified as a cause for increased mitochondrial capacity in Prep1 ablated mice. Prep1 stabilizes p160 Mybbp1a, a known inhibitor of PGC-1α activity. Thereby, p160 protein levels were significantly lower in the muscle of Prep1 ablated mice. By a chromatin immunoprecipitation-sequencing (ChIP-seq) approach, PREP1 binding sites in genes encoding mitochondrial components (e.g., Ndufs2) were identified that might be responsible for elevated proteins involved in oxidative phosphorylation (OXPHOS) in the muscle of Prep1 null mutants. These results suggest that Prep1 exhibits additional direct effects on regulation of mitochondrial proteins. We therefore conclude that Prep1 is a regulator of oxidative phosphorylation components via direct and indirect mechanisms.
Department of Experimental Diabetology, German Institute of Human Nutrition, Potsdam-Rehbruecke, Germany.
Timo
T
Kanzleiter
Michaela
M
Rath
Dmitry
D
Penkov
Dmytro
D
Puchkov
Nadja
N
Schulz
Francesco
F
Blasi
Annette
A
Schürmann
D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins; D004579:Electron Transport; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D004734:Energy Metabolism; D005260:Female; D015870:Gene Expression; D018398:Homeodomain Proteins / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008931:Mitochondria, Muscle / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D010085:Oxidative Phosphorylation; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010641:Phenotype; D010807:Physical Endurance; D011401:Promoter Regions, Genetic; D021122:Protein Subunits / Q000378:metabolism; D016601:RNA-Binding Proteins; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D045222:Electron Transport Chain Complex Proteins; D018398:Homeodomain Proteins; C110421:Mybbp1a protein, mouse; D009687:Nuclear Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C491412:Pknox1 protein, mouse; C485290:Ppargc1a protein, mouse; D021122:Protein Subunits; D016601:RNA-Binding Proteins; D014157:Transcription Factors