Comprehensive Physiology Wiley Online Library

Regulation of Mitochondrial Biogenesis and GLUT4 Expression by Exercise

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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 Ca2+ and decreases in ATP and creatine phosphate (∼P). Ca2+ 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.

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Further Reading
 1. Hood DA. Mechanisms of exercise‐induced mitochondrial biogenesis in skeletal muscle. Appl Physiol Nutr Metab 34: 465–472, 2009.
 2. Jensen TE, Wojtaszewski JFP, Richter EA. AMP‐activated protein kinase in contraction regulation of skeletal muscle metabolism: Necessary and/or sufficient. Acta Physiol 196: 155–174, 2009.
 3. Lanza IR, Nair KS. Muscle mitochondrial changes with aging and exercise. Am J Clin Nutr 89: 467S–471S, 2009.
 4. Lanza IR, Short DK, Short KR, Raghavakaimal S, Basu R, Joyner MJ, McConnell JP, Nair KS. Endurance exercise as a countermeasure for aging. Diabetes 57: 2933–2942, 2008.
 5. Lira VA, Benton CR, Yan Z, Bonen A. PGC‐1 a regulation by exercise training and its influences on muscle function and insulin sensitivity. Am J Physiol Endocrinol Metab 299: E145–E161, 2010.
 6. Ljubicic V, Joseph AM, Saleem A, Uguccioni G, Collu‐Marchese M, Lai RY, Nguyen LM, Hood DA. Transcriptional and post‐transcriptional regulation of mitochondrial biogenesis in skeletal muscle: Effects of exercise and aging. Biochim Biophys Acta 1800: 223–234, 2010.
 7. Scarpulla RC. Transcriptional paradigms in mammalian mitochondrial biogenesis and function. Physiol Rev 88: 611–638, 2008.


Further Reading

Hood DA. Mechanisms of exercise-induced mitochondrial biogenesis in skeletal muscle. Appl Physiol Nutr Metab 34: 465-472, 2009.

Jensen TE, Wojtaszewski JFP and Richter EA. AMP-activated protein kinase in contraction regulation of skeletal muscle metabolism: necessary and/or sufficient? Acta Physiol 196: 155-174, 2009.

 Lanza IR and Nair KS. Muscle mitochondrial changes with aging and exercise. Am J Clin Nutr 89: 467S-471S, 2009.

Lanza IR, Short DK, Short KR, Raghavakaimal S, Basu R, Joyner MJ, McConnell JP and Nair KS. Endurance exercise as a countermeasure for aging. Diabetes 57: 2933-2942, 2008.

Lira VA, Benton CR, Yan Z and Bonen A. PGC-1 regulation by exercise training and its influences on muscle function and insulin sensitivity. Am J Physiol Endocrinol Metab 299: E145-E161, 2010.

Ljubicic V, Joseph AM, Saleem A, Uguccioni G, Collu-Marchese M, Lai RY, Nguyen LM and Hood DA. Transcriptional and post-transcriptional regulation of mitochondrial biogenesis in skeletal muscle: effects of exercise and aging. Biochim Biophys Acta 1800: 223-234, 2010.

Scarpulla RC. Transcriptional paradigms in mammalian mitochondrial biogenesis and function. Physiol Rev 88: 611-638, 2008.


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John O. Holloszy. Regulation of Mitochondrial Biogenesis and GLUT4 Expression by Exercise. Compr Physiol 2011, 1: 921-940. doi: 10.1002/cphy.c100052