PPARβ Is Essential for Maintaining Normal Levels of PGC-1α and Mitochondria and for the Increase in Muscle Mitochondria Induced by Exercise

• Published in: Cell metabolism 2017-05, Vol.25 (5), p.1176-1185.e5
• Main Authors: Koh, Jin-Ho, Hancock, Chad R., Terada, Shin, Higashida, Kazuhiko, Holloszy, John O., Han, Dong-Ho
• Format: Article
• Language: English
• Subjects: AMP-Activated Protein Kinases - metabolism; Animals; Calcium-Calmodulin-Dependent Protein Kinase Kinase - genetics; Cell Line; Enzyme Activation; Gene Knockdown Techniques; HEK293 Cells; Humans; Male; Mice, Inbred C57BL; mitochondria; Mitochondria, Muscle - genetics; Mitochondria, Muscle - metabolism; muscle; NRF-1; Nuclear Respiratory Factor 1 - genetics; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism; PGC-1α; Physical Conditioning, Animal; PPAR-beta - genetics; PPAR-beta - metabolism; PPARβ; Proteolysis; Rats, Wistar; Transcriptional Activation; Ubiquitination; Up-Regulation
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2017.04.029

The objective of this study was to evaluate the specific mechanism(s) by which PPARβ regulates mitochondrial content in skeletal muscle. We discovered that PPARβ increases PGC-1α by protecting it from degradation by binding to PGC-1α and limiting ubiquitination. PPARβ also induces an increase in nuclear respiratory factor 1 (NRF-1) expression, resulting in increases in mitochondrial respiratory chain proteins and MEF2A, for which NRF-1 is a transcription factor. There was also an increase in AMP kinase phosphorylation mediated by an NRF-1-induced increase in CAM kinase kinase-β (CaMKKβ). Knockdown of PPARβ resulted in large decreases in the levels of PGC-1α and mitochondrial proteins and a marked attenuation of the exercise-induced increase in mitochondrial biogenesis. In conclusion, PPARβ induces an increase in PGC-1α protein, and PPARβ is a transcription factor for NRF-1. Thus, PPARβ plays essential roles in the maintenance and adaptive increase in mitochondrial enzymes in skeletal muscle by exercise. [Display omitted] •PPARβ increases PGC-1α content via a reduction in protein degradation•PPARβ promotes transcription of nuclear respiratory factor 1 (NRF-1)•NRF-1 increases transcription of CaMKKβ and activation of AMPK•PPARβ is essential for the maintenance of and increase in mitochondrial enzymes PPARβ is essential in modulating mitochondria in skeletal muscle during exercise. Koh et al. show that there are two phases of adaptation: an initial direct one whereby PPARβ promotes NRF-1 transcription, in turn leading to CaMKKβ transcription and activation of AMPK, and a later one by inhibiting PGC-1α protein degradation.