From the perspective of a molecular biologist, maximizing mitochondria and blood vessels in fibers of the largest motor units is the role of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) and its binding partners. It has been known for over a decade that simply increasing PGC-1α can drive the formation of new mitochondria within a muscle [5]. More recently, PGC-1α has been shown to play a role in the control of fat oxidation and angiogenesis, suggesting that the adaptation to endurance exercise is mediated by PGC-1α. As PGC-1α is rapidly activated by endurance exercise [6, 7], this suggests that training should be designed to maximize PGC-1α activation. Naturally, this is an oversimplification. The regulation of mitochondrial mass is essential to organismal fitness and therefore redundancy has evolved to protect the organism from catastrophic failure. As a result of these redundant genes, muscles that lack PGC-1α are still able to increase mitochondria in response to exercise training [8]. However, without PGC-1α basal metabolic function is reduced because of a reduction in proteins of the electron transport chain and maximum aerobic capacity is dramatically reduced.

PGC-1α is a transcriptional coactivator, a protein that increases transcription without binding directly to DNA. Instead, PGC-1α interacts with transcription factors that bind to DNA in a sequence-specific manner. Therefore, the transcription factors identify the specific genes to turn on, whereas PGC-1α determines the volume. For example, by interacting with the nuclear response factors, PGC-1α can increase mitochondria [5]; by interacting with the peroxisome proliferator-activated receptors, PGC-1α increases fat oxidation proteins [9]; and by interacting with the estrogen-related receptor α, PGC-1α increases blood vessels [10]. Therefore in many ways, together with its binding partners, PGC-1α induces all of the muscular adaptations to endurance exercise.

If the key to future performance is the repeated activation of PGC-1α in training, the question becomes how can PGC-1α activity be maximized? PGC-1α is activated in two ways. First, existing PGC-1α protein can be modified either to make it go into the nucleus, where transcription takes place, or increase its ability to interact with its binding partners. There are two ways that it is known PGC-1α is modified: phosphorylation and acetylation [11, 12]. PGC-1α is most active when it is more phosphorylated and less acetylated. At the most basic level, phosphorylation is the addition of a negatively charged phosphate group to a protein. By a similar token, acetylation is the functional removal of a positive charge from a protein through the addition of a neutral acetyl group to a positively charged lysine residue. Therefore, PGC-1α is most active when it has more regions of positive and negative charges. The importance of the charge density on PGC-1α activity suggests that its translocation into the nucleus and its ability to interact with transcription factors is dependent on hydrogen bonding (the positive amino acids in one protein binding with the negative amino acids in another protein). Therefore, more phosphorylation and less acetylation equates to more negative and positive charges, better binding between PGC-1α and chaperone/transcription factors, and therefore higher transcriptional activity.

The second way to increase PGC-1α activity is to make more of the protein. The amount of PGC-1α protein is regulated transcriptionally through more than one promoter [13]. The canonical promoter is active ubiquitously, whereas the alternative promoter produces messenger RNA only in muscle and brown fat [10]. The gene products from the two promoters have been renamed to minimize confusion. Protein produced from the canonical promoter is now called PGC-1α1, whereas the protein from the alternative promoters are called PGC1α2-4 [10]. It was originally shown that following an acute bout of endurance exercise there was a rapid and profound increase in PGC-1α mRNA made from the alternative promoter (Fig. 1) [6]. The product of this alternative promoter is significantly shorter and is only expressed at high levels following exercise in both rodents [6] and humans [14]. The complex regulation of PGC-1α2 transcription by exercise has been elucidated over the past decade with the bulk of this work elegantly described in one paper by Akimoto et al. [15] and summarized below.