Every time a bout of exercise is performed, a change in gene expression occurs within the contracting muscle. Over the course of many repeated bouts of exercise (i.e. training), the cumulative effects of these alterations lead to a change in muscle phenotype. One of the most prominent of these adaptations is an increase in mitochondrial content, which confers a greater resistance to muscle fatigue. This essay reviews current knowledge on the regulation of exercise-induced mitochondrial biogenesis at the molecular level. The major steps involved include, (i) transcriptional regulation of nuclear-encoded genes encoding mitochondrial proteins by the coactivator peroxisome-proliferator-activated receptor g coactivator-1, (ii) control of mitochondrial DNA gene expression by the transcription factor Tfam, (iii) mitochondrial fission and fusion mechanisms, and (iv) import of nuclear-derived gene products into the mitochondrion via the protein import machinery. It is now known that exercise can modify the rates of several of these steps, leading to mitochondrial biogenesis. An understanding of how exercise can produce this effect could help us decide whether exercise is beneficial for patients suffering from mitochondrial disorders, as well as a variety of metabolic diseases.

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Myogenesis involves the fusion of myoblasts into myotubes. Mitochondrial biogenesis plays an important role in myogenesis, but the molecular mechanisms that govern the changes in mitochondria during differentiation have yet to be fully elucidated. Thus, we sought to describe the regulation of mitochondrial biogenesis during 8 days of C2C12 myoblast differentiation in culture. Cytochrome c oxidase (COX) activity, a marker of biogenesis, was increased by 2.6‐fold during differentiation. The mRNAs encoding the fusion protein mitofusin‐2 (Mfn2) increased by 20–30 fold by day 4, while no changes were observed in Fis1, a fission protein. This coincided with an increase in mitochondrial network formation, and a decrease in organelle granularity. Mitochondrial transcription factor A (Tfam) and COX subunit IV (COX IV) protein levels increased during differentiation, but no changes in mRNA levels were evident. Thus, differentiation of C2C12 cells promotes mitochondrial biogenesis via: mitochondrial fusion through an increase in the Mfn2‐to‐Fis1 ratio, increases in Tfam, the regulator of mtDNA gene transcription and translation. These changes contribute to the increase in mitochondrial function and content, evident from the changes in COX enzyme activity. These data suggest a well regulated pattern of gene expression that occurs during differentiation leading to mitochondrial biogenesis.

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