Regulation of Mitochondrial Biogenesis and GLUT4 Expression by Exercise

Abstract Endurance exercise training can induce large increases mitochondria and the GLUT4 isoform of the glucose transporter in skeletal muscle. For a long time after the discovery in the 1960s that exercise results in an increase in muscle mitochondria, there was no progress in elucidation of the mechanisms involved. The reason for this lack of progress was that nothing was known regarding how expression of the genes‐encoding mitochondrial proteins is coordinately regulated. This situation changed rapidly after discovery of transcription factors that control transcription of genes‐encoding mitochondrial proteins and, most importantly, the discovery of peroxisome proliferator‐gamma coactivator‐1α (PGC‐1α). This transcription coactivator binds to and activates transcription factors that regulate transcription of genes‐encoding mitochondrial proteins. Thus, PGC‐1α activates and coordinates mitochondrial biogenesis. It is now known that exercise rapidly activates and induces increased expression of PGC‐1α. The exercise‐generated signals that lead to PGC‐1α activation and increased expression are the increases in cytosolic Ca 2+ and decreases in ATP and creatine phosphate (∼P). Ca 2+ mediates its effect by activating CAMKII, while the decrease in ∼P mediates its effect via activation of AMPK. Expression of the GLUT4 isoform of the glucose transporter is regulated in parallel with mitochondrial biogenesis via the same signaling pathways. This review describes what is known regarding the regulation of mitochondrial biogenesis and GLUT4 expression by exercise. A major component of this review deals with the physiological and metabolic consequences of the exercise‐induced increase in mitochondria and GLUT4. © 2011 American Physiological Society. Compr Physiol 1:921‐940, 2011.