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

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Abstract
The transcriptional coactivator the peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) 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-1α protein expression under conditions that provoke mitochondrial biogenesis, such as contractile activity or thyroid hormone (T3) treatment, is not fully characterized. Thus we related PGC-1α protein expression to cytochrome c oxidase (COX) activity in 1) tissues of varying oxidative capacities, 2) tissues from animals treated with T3, 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-1α and COX activity, used as an index of mitochondrial adaptations. The highest constitutive levels of PGC-1α were found in the heart, whereas the lowest were measured in fast-twitch white muscle and liver. T3 increased PGC-1α content similarly in both fast- and slow-twitch muscle, as well as in the liver, but not in heart. T3 also induced early (6 h) increases in AMP-activated protein kinase (AMPKα) 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-1α, coincident with increases in mitochondrial transcription factor A (Tfam), and nuclear respiratory factor-1 (NRF-1) protein expression, suggesting that PGC-1α is physiologically important in coordinating the expression of the nuclear and mitochondrial genomes. Ca2+ ionophore treatment of muscle cells led to an approximately threefold increase in PGC-1α protein, and contractile activity induced rapid and marked increases in both p38 MAP kinase and AMPKα activities. 5-Aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) treatment of muscle cells also led to parallel increases in AMPKα activity and PGC-1α protein levels. These data are consistent with observations that indicate that increases in PGC-1α protein are affected by Ca2+ signaling mechanisms, AMPKα activity, as well as posttranslational phosphorylation events that increase PGC-1α protein stability. Our data support a role for PGC-1α in the physiological regulation of mitochondrial content in a variety of tissues and suggest that increases in PGC-1α expression form part of a unifying pathway that promotes both T3- and contractile activity-induced mitochondrial adaptations.

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