PPARγ coactivator-1α expression during thyroid hormone- and contractile activity-induced mitochondrial adaptations

Abstract

The transcriptional coactivator the peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) has been identified as an important mediator of mitochondrial biogenesis based on its ability to interact with transcription factors that activate nuclear genes encoding mitochondrial proteins. The induction of PGC-1alpha protein expression under conditions that provoke mitochondrial biogenesis, such as contractile activity or thyroid hormone (T(3)) treatment, is not fully characterized. Thus we related PGC-1alpha protein expression to cytochrome c oxidase (COX) activity in 1) tissues of varying oxidative capacities, 2) tissues from animals treated with T(3), and 3) skeletal muscle subject to contractile activity both in cell culture and in vivo. Our results demonstrate a strong positive correlation (r = 0.74; P < 0.05) between changes in PGC-1alpha and COX activity, used as an index of mitochondrial adaptations. The highest constitutive levels of PGC-1alpha were found in the heart, whereas the lowest were measured in fast-twitch white muscle and liver. T(3) increased PGC-1alpha content similarly in both fast- and slow-twitch muscle, as well as in the liver, but not in heart. T(3) also induced early (6 h) increases in AMP-activated protein kinase (AMPKalpha) activity, as well as later (5 day) increases in p38 MAP kinase activity in slow-twitch, but not in fast-twitch, muscle. Contractile activity provoked early increases in PGC-1alpha, coincident with increases in mitochondrial transcription factor A (Tfam), and nuclear respiratory factor-1 (NRF-1) protein expression, suggesting that PGC-1alpha is physiologically important in coordinating the expression of the nuclear and mitochondrial genomes. Ca(2+) ionophore treatment of muscle cells led to an approximately threefold increase in PGC-1alpha protein, and contractile activity induced rapid and marked increases in both p38 MAP kinase and AMPKalpha activities. 5-Aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR) treatment of muscle cells also led to parallel increases in AMPKalpha activity and PGC-1alpha protein levels. These data are consistent with observations that indicate that increases in PGC-1alpha protein are affected by Ca(2+) signaling mechanisms, AMPKalpha activity, as well as posttranslational phosphorylation events that increase PGC-1alpha protein stability. Our data support a role for PGC-1alpha in the physiological regulation of mitochondrial content in a variety of tissues and suggest that increases in PGC-1alpha expression form part of a unifying pathway that promotes both T(3)- and contractile activity-induced mitochondrial adaptations.

Age associated low mitochondrial biogenesis may be explained by lack of response of PGC-1α to exercise training

“…Two of the key stimulators of PGC-1α are thyroid hormones (Irrcher et al 2003) and cold exposure (Puigserver et al 1998). Figure 4a shows that young animals, when exposed to cold, upregulated the For the densitometric analysis of the results values are shown as mean (±SD) of a WT untrained (n=6), WT trained (n=8), PGC-1α KO untrained (n=7), and PGC-1α KO-trained animals (n=6); b young untrained (n=6), young trained (n=6), aged untrained (n=6), and aged-trained animals (n=6) expression of PGC-1α threefold but aged animals did not.…”

“…We suspected that PGC-1α might not be induced by any kind of stimulus in old animals. To test this hypothesis, we used two well-known stimuli of PGC-1α in young and old rats, namely thyroid hormone stimulation and cold acclimation (Irrcher et al 2003;Puigserver et al 1998). Figure 4 shows that both T3 treatment or cold acclimatization caused a very pronounced activation of PGC-1α in young animals.…”

“…Skeletal muscles were removed 6 h after the injections (Irrcher et al 2003). Gastrocnemius and soleus muscles were removed quickly, freeze-clamped immediately, and stored at −80°C.…”

Irisin and FNDC5: effects of 12-week strength training, and relations to muscle phenotype and body mass composition in untrained women

“…This may be linked to the fact that low-intensity every-day activities such as walking, which preferentially activate type 1 fibers, may lead to increased nuclear translocation of PGC1α, in turn leading to the observed fiber-specific FNDC5 expression. Indeed, slow-fibre patterned electrical activity has been shown to be capable of resulting in increased PGC1α protein abundance in both rodents and humans (Irrcher et al 2003;Gundersen 2011;Adams et al 2011). Alternatively, it may point to a housekeeping-resembling manner of regulation of irisin biology, wherein FNDC5 expression and irisin secretion is a passive consequence of muscle fiber composition.…”

“…In addition to being functionally related to irisin, as important regulators of whole-body metabolism, T3 has been shown to lead to increased levels of PGC-1α protein in skeletal muscle tissue (Irrcher et al 2003), providing a potential molecular link between T3 and FNDC5. Indeed, T3 supplementation of rats has even been shown to lead to increased levels of FNDC5 expression in brain, constituting one of a mere 149 up-regulated genes (Diez et al 2008).…”