Fig. 1. Mitochondrial biogenesis is a component of contractile activity-induced muscle plasticity. Skeletal muscle contractile activity (1) is associated with elevations in intracellular Ca²⁺ and the subsequent activation of Ca²⁺-sensitive signaling molecules such as calcium/calmodulin-dependent protein kinase (CaMK). In addition, ATP turnover resulting in the rise of AMP leads to the activation of AMP-activated protein kinase (AMPK). These two signaling kinases translocate to the myonuclei (2) and positively influence gene transcription through their interactions with the transcriptional co-activator peroxisome proliferator-activated receptor- coactivator-1 (PGC-1). PGC-1 autoregulates its gene expression, along with the expression of nuclear respiratory factor-1 (NRF-1) and NRF-2. NRF-1 and NRF-2 are transcription factors for numerous nuclear genes encoding mitochondrial proteins (NUGEMPS). NRF-1 also induces the expression of mitochondrial transcription factor A (Tfam), which, along with other nuclear-encoded mitochondrial proteins (NEMPS), is imported (3) into mitochondria by the protein import machinery (PIM). Tfam regulates the expression of the 13 mitochondrial DNA (mtDNA) gene products, including proteins such as cytochrome c oxidase subunit I (COX I). NEMPS and mtDNA-encoded proteins are assembled to form multi-subunit enzyme complexes required for oxygen consumption and ATP synthesis. This coordination between nuclear and mitochondrial genomes is necessary for organelle biogenesis. The mitochondrial phenotype is also altered through fusion and fission events (4). Mitofusion-2 (Mfn-2) influences the fusion of discrete populations of mitochondria into a larger mitochondrial reticulum, whereas Fis 1 is an important protein involved in organelle fission. Mitochondrial membrane potential () is associated with the production of reactive oxygen species (ROS) from within the ETC, both of which can be reduced by the activity of uncoupling protein-3 (UCP3). Elevated ROS levels can trigger the opening of the mitochondrial permeability transition pore (mtPTP) and the release of the pro-apoptotic factors cytochrome c and apoptosis-inducing factor (AIF). Liberation of these proteins is the primary step in the mitochondrially mediated apoptotic program (5). Execution of this program is also facilitated by the actions of p53 and its downstream transcriptional target BAX. The anti-aging protein SIRT1 can inhibit the p53 pathway leading to apoptosis and it is known to negatively regulate hepatic PGC-1 activity. The actions of SIRT1 in muscle remain unresolved.