Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is a protein that in humans is encoded by the PPARGC1Agene.[4] PPARGC1A is also known as human accelerated region 20 (HAR20). It may, therefore, have played a key role in differentiating humans from apes.[5]
PGC-1α is a gene that contains two promoters, and has 4 alternative splicings. PGC-1α is a transcriptional coactivator that regulates the genes involved in energy metabolism. It is the master regulatorofmitochondrial biogenesis.[6][7][8] This protein interacts with the nuclear receptorPPAR-γ, which permits the interaction of this protein with multiple transcription factors. This protein can interact with, and regulate the activity of, cAMP response element-binding protein (CREB) and nuclear respiratory factors (NRFs)[citation needed]. PGC-1α provides a direct link between external physiological stimuli and the regulation of mitochondrial biogenesis, and is a major factor causing slow-twitch rather than fast-twitch muscle fiber types.[10]
Fasting can also increase gluconeogenic gene expression, including hepatic PGC-1α.[16][17]
It is strongly induced by cold exposure, linking this environmental stimulus to adaptive thermogenesis.[18]
It is induced by endurance exercise[11] and recent research has shown that PGC-1α determines lactate metabolism, thus preventing high lactate levels in endurance athletes and making lactate as an energy source more efficient.[19]
cAMP response element-binding (CREB) proteins, activated by an increase in cAMP following external cellular signals.
Protein kinase B (Akt) is thought to downregulate PGC-1α, but upregulate its downstream effectors, NRF1 and NRF2. Akt itself is activated by PIP3, often upregulated by PI3K after G protein signals. The Akt family is also known to activate pro-survival signals as well as metabolic activation.
Akt and calcineurin are both activators of NF-kappa-B (p65).[23][24] Through their activation, PGC-1α seems to activate NF-kappa-B. Increased activity of NF-kappa-B in muscle has recently been demonstrated following induction of PGC-1α.[25] The finding seems to be controversial. Other groups found that PGC-1s inhibit NF-kappa-B activity.[26] The effect was demonstrated for PGC-1 alpha and beta.
Massage therapy appears to increase the amount of PGC-1α, which leads to the production of new mitochondria.[31][32][33]
PGC-1α and beta has furthermore been implicated in polarization to anti-inflammatory M2 macrophages by interaction with PPAR-γ[34] with upstream activation of STAT6.[35] An independent study confirmed the effect of PGC-1 on polarisation of macrophages towards M2 via STAT6/PPAR gamma and furthermore demonstrated that PGC-1 inhibits proinflammatory cytokine production.[36]
PGC-1α has been recently proposed to be responsible for β-aminoisobutyric acid secretion by exercising muscles.[37] The effect of β-aminoisobutyric acid in white fat includes the activation of thermogenic genes that prompt the browning of white adipose tissue and the consequent increase of background metabolism. Hence, the β-aminoisobutyric acid could act as a messenger molecule of PGC-1α and explain the effects of PGC-1α increase in other tissues such as white fat.
PGC-1α increases BNP expression by coactivating ERRα and / or AP1. Subsequently, BNP induces a chemokine cocktail in muscle fibers and activates macrophages in a local paracrine manner, which can then contribute to enhancing the repair and regeneration potential of trained muscles.
Most studies reporting effects of PGC-1α on physiological functions have used mouse models in which the PGC-1α gene is either knocked out or overexpressed from conception. However, some of the proposed effects of PGC-1α have been questioned by studies using inducible knockout technology to remove the PGC-1α gene only in adult mice. For example, two independent studies have shown that adult expression of PGC-1α is not required for improved mitochondrial function after exercise training.[38][39] This suggests that some of the reported effects of PGC-1α are likely to occur only in the developmental stage.
^ abValero T (2014). "Mitochondrial biogenesis: pharmacological approaches". Curr. Pharm. Des.20 (35): 5507–9. doi:10.2174/138161282035140911142118. hdl:10454/13341. PMID24606795. Mitochondrial biogenesis is therefore defined as the process via which cells increase their individual mitochondrial mass [3]. ... This work reviews different strategies to enhance mitochondrial bioenergetics in order to ameliorate the neurodegenerative process, with an emphasis on clinical trials reports that indicate their potential. Among them creatine, Coenzyme Q10 and mitochondrial targeted antioxidants/peptides are reported to have the most remarkable effects in clinical trials.
^ abSanchis-Gomar F, García-Giménez JL, Gómez-Cabrera MC, Pallardó FV (2014). "Mitochondrial biogenesis in health and disease. Molecular and therapeutic approaches". Curr. Pharm. Des. 20 (35): 5619–5633. doi:10.2174/1381612820666140306095106. PMID24606801. Mitochondrial biogenesis (MB) is the essential mechanism by which cells control the number of mitochondria.
^Yakeu G, Butcher L, Isa S, Webb R, Roberts AW, Thomas AW, Backx K, James PE, Morris K (October 2010). "Low-intensity exercise enhances expression of markers of alternative activation in circulating leukocytes: roles of PPARγ and Th2 cytokines". Atherosclerosis. 212 (2): 668–73. doi:10.1016/j.atherosclerosis.2010.07.002. PMID20723894.
Overview of all the structural information available in the PDB for UniProt: Q9UBK2 (Peroxisome proliferator-activated receptor gamma coactivator 1-alpha) at the PDBe-KB.