Schematic representation of metabolic pathway changes in PGC-1α-Tg mice.

<p>The levels of many metabolic products are changed in the skeletal muscle of PGC-1α-Tg mice. Many of these changes are associated with mitochondrial metabolism, in particular the TCA cycle. Increased mitochondrial content due to PGC-1α-overexpression appears to activate the TCA cycle (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0129084#pone.0129084.g003" target="_blank">Fig 3</a>); therefore, there must be more substrates available for the TCA cycle. For instance, the activated pentose phosphate pathway (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0129084#pone.0129084.g004" target="_blank">Fig 4</a>) stimulates nucleotide synthesis (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0129084#pone.0129084.g005" target="_blank">Fig 5</a>), which is followed by activation of the purine nucleotide cycle (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0129084#pone.0129084.g006" target="_blank">Fig 6</a>), supplying fumarate for the TCA cycle. Meanwhile, activation of the malate-aspartate shuttle supplies other substrates (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0129084#pone.0129084.g007" target="_blank">Fig 7</a>). In addition, amino acids are also likely to be used as substrates (Figs <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0129084#pone.0129084.g007" target="_blank">7</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0129084#pone.0129084.g008" target="_blank">8</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0129084#pone.0129084.g009" target="_blank">9</a>). Increased coordinated regulation of the TCA cycle and amino acid metabolism, including BCAA, suggests that PGC-1α plays important roles in energy metabolism. Moreover, activation of the purine nucleotide pathway and malate–aspartate shuttle, which are known to be active during exercise, further suggests that PGC-1α regulates metabolism in exercise.