Inadequate physical activity is linked to many chronic diseases. But the mechanisms that tie muscle activity to health are unclear. The transcriptional coactivator PGC1α has recently been shown to regulate several exercise-associated aspects of muscle function. We propose that this protein controls muscle plasticity, suppresses a broad inflammatory response and mediates the beneficial effects of exercise.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Booth, F. W., Chakravarthy, M. V., Gordon, S. E. & Spangenburg, E. E. Waging war on physical inactivity: using modern molecular ammunition against an ancient enemy. J. Appl. Physiol. 93, 3–30 (2002).
Erikssen, G. et al. Changes in physical fitness and changes in mortality. Lancet 352, 759–762 (1998).
Hu, F. B. et al. Adiposity as compared with physical activity in predicting mortality among women. N. Engl. J. Med. 351, 2694–2703 (2004).
Kokkinos, P. et al. Exercise capacity and mortality in black and white men. Circulation 117, 614–622 (2008).
Booth, F. W. & Lees, S. J. Fundamental questions about genes, inactivity, and chronic diseases. Physiol. Genomics 28, 146–157 (2007).
McCracken, M., Jiles, R. & Blanck, H. M. Health behaviors of the young adult U.S. population: behavioral risk factor surveillance system, 2003. Prev. Chronic Dis. 4, A25 (2007).
Hollmann, W., Struder, H. K., Tagarakis, C. V. & King, G. Physical activity and the elderly. Eur. J. Cardiovasc. Prev. Rehabil. 14, 730–739 (2007).
Yates, L. B. et al. Exceptional longevity in men: modifiable factors associated with survival and function to age 90 years. Arch. Intern. Med. 168, 284–290 (2008).
Knowler, W. C. et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N. Engl. J. Med. 346, 393–403 (2002).
Hotamisligil, G. S. Inflammation and metabolic disorders. Nature 444, 860–867 (2006).
Haffner, S. M. The metabolic syndrome: inflammation, diabetes mellitus, and cardiovascular disease. Am. J. Cardiol. 97, 3A–11A (2006).
Matter, C. M. & Handschin, C. RANTES (regulated on activation, normal T cell expressed and secreted), inflammation, obesity, and the metabolic syndrome. Circulation 115, 946–948 (2007).
Lin, W. W. & Karin, M. A cytokine-mediated link between innate immunity, inflammation, and cancer. J. Clin. Invest. 117, 1175–1183 (2007).
Zhou, J. R., Blackburn, G. L. & Walker, W. A. Symposium introduction: metabolic syndrome and the onset of cancer. Am. J. Clin. Nutr. 86, S817–S819 (2007).
Tansey, M. G. et al. Neuroinflammation in Parkinson's disease: is there sufficient evidence for mechanism-based interventional therapy? Front. Biosci. 13, 709–717 (2008).
Whitton, P. S. Inflammation as a causative factor in the aetiology of Parkinson's disease. Br. J. Pharmacol. 150, 963–976 (2007).
Zipp, F. & Aktas, O. The brain as a target of inflammation: common pathways link inflammatory and neurodegenerative diseases. Trends Neurosci. 29, 518–527 (2006).
Cotman, C. W., Berchtold, N. C. & Christie, L. A. Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci. 30, 464–472 (2007).
Perry, V. H., Cunningham, C. & Holmes, C. Systemic infections and inflammation affect chronic neurodegeneration. Nature Rev. Immunol. 7, 161–167 (2007).
Febbraio, M. A. Exercise and inflammation. J. Appl. Physiol. 103, 376–377 (2007).
Gleeson, M. Immune function in sport and exercise. J. Appl. Physiol. 103, 693–699 (2007).
Nieman, D. C. Current perspective on exercise immunology. Curr. Sports Med. Rep. 2, 239–242 (2003).
Gleeson, M., McFarlin, B. & Flynn, M. Exercise and Toll-like receptors. Exerc. Immunol. Rev. 12, 34–53 (2006).
Gleeson, M., Nieman, D. C. & Pedersen, B. K. Exercise, nutrition and immune function. J. Sports Sci. 22, 115–125 (2004).
Pedersen, B. K., Akerstrom, T. C., Nielsen, A. R. & Fischer, C. P. Role of myokines in exercise and metabolism. J. Appl. Physiol. 103, 1093–1098 (2007).
Kristiansen, O. P. & Mandrup-Poulsen, T. Interleukin-6 and diabetes: the good, the bad, or the indifferent? Diabetes 54, S114–S124 (2005).
Sarkar, D. & Fisher, P. B. Molecular mechanisms of aging-associated inflammation. Cancer Lett. 236, 13–23 (2006).
Bremmer, M. A. et al. Inflammatory markers in late-life depression: Results from a population-based study. J. Affect. Disord. 106, 249–255 (2008).
Roubenoff, R. Physical activity, inflammation, and muscle loss. Nutr. Rev. 65, S208–S212 (2007).
Haddad, F., Zaldivar, F., Cooper, D. M. & Adams, G. R. IL-6-induced skeletal muscle atrophy. J. Appl. Physiol. 98, 911–917 (2005).
Coletti, D. et al. Tumor necrosis factor-α gene transfer induces cachexia and inhibits muscle regeneration. Genesis 43, 120–128 (2005).
Manson, J. E. et al. A prospective study of walking as compared with vigorous exercise in the prevention of coronary heart disease in women. N. Engl. J. Med. 341, 650–658 (1999).
Thomas, D. R. Loss of skeletal muscle mass in aging: examining the relationship of starvation, sarcopenia and cachexia. Clin. Nutr. 26, 389–399 (2007).
Sigal, R. J. et al. Effects of aerobic training, resistance training, or both on glycemic control in type 2 diabetes: a randomized trial. Ann. Intern. Med. 147, 357–369 (2007).
Larson, E. B. et al. Exercise is associated with reduced risk for incident dementia among persons 65 years of age and older. Ann. Intern. Med. 144, 73–81 (2006).
Pette, D. Historical perspectives: plasticity of mammalian skeletal muscle. J. Appl. Physiol. 90, 1119–1124 (2001).
Flück, M. & Hoppeler, H. Molecular basis of skeletal muscle plasticity — from gene to form and function. Rev. Physiol. Biochem. Pharmacol. 146, 159–216 (2003).
Glass, D. J. Skeletal muscle hypertrophy and atrophy signaling pathways. Int. J. Biochem. Cell Biol. 37, 1974–1984 (2005).
Chin, E. R. et al. A calcineurin-dependent transcriptional pathway controls skeletal muscle fiber type. Genes Dev. 12, 2499–2509 (1998).
Berchtold, M. W., Brinkmeier, H. & Muntener, M. Calcium ion in skeletal muscle: its crucial role for muscle function, plasticity, and disease. Physiol. Rev. 80, 1215–1265 (2000).
Puigserver, P. et al. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92, 829–839 (1998).
Pilegaard, H., Saltin, B. & Neufer, P. D. Exercise induces transient transcriptional activation of the PGC-1α gene in human skeletal muscle. J. Physiol. 546, 851–858 (2003).
Hood, D. A., Irrcher, I., Ljubicic, V. & Joseph, A. M. Coordination of metabolic plasticity in skeletal muscle. J. Exp. Biol. 209, 2265–2275 (2006).
Jager, S., Handschin, C., St-Pierre, J. & Spiegelman, B. M. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α. Proc. Natl Acad. Sci. USA 104, 12017–12022 (2007).
Russell, A. P. et al. Endurance training in humans leads to fiber type-specific increases in levels of peroxisome proliferator-activated receptor-γ coactivator-1 and peroxisome proliferator-activated receptor-α in skeletal muscle. Diabetes 52, 2874–2881 (2003).
Lin, J. et al. Transcriptional co-activator PGC-1α drives the formation of slow-twitch muscle fibres. Nature 418, 797–801 (2002).
Calvo, J. A. et al. Muscle-specific expression of PPARγ coactivator-1α improves exercise performance and increases peak oxygen uptake. J. Appl. Physiol. 104, 1304–1312 (2008).
Wende, A. R. et al. A role for the transcriptional coactivator PGC-1α in muscle refueling. J. Biol. Chem. 282, 36642–36651 (2007).
Handschin, C. et al. Skeletal muscle fiber-type switching, exercise intolerance, and myopathy in PGC-1α muscle-specific knock-out animals. J. Biol. Chem. 282, 30014–30021 (2007).
Handschin, C. & Spiegelman, B. M. Peroxisome proliferator-activated receptor γ coactivator 1 coactivators, energy homeostasis, and metabolism. Endocr. Rev. 27, 728–735 (2006).
Lin, J., Handschin, C. & Spiegelman, B. M. Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab. 1, 361–370 (2005).
Hanai, J. I. et al. The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity. J. Clin. Invest. 117, 3940–3951 (2007).
Handschin, C. et al. PGC-1α regulates the neuromuscular junction program and ameliorates Duchenne muscular dystrophy. Genes Dev. 21, 770–783 (2007).
Sandri, M. et al. PGC-1α protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription. Proc. Natl Acad. Sci. USA 103, 16260–16265 (2006).
Wu, Z. et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98, 115–124 (1999).
Mootha, V. K. et al. Errα and Gabpa/b specify PGC-1α-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle. Proc. Natl Acad. Sci. USA 101, 6570–6575 (2004).
Handschin, C. et al. Abnormal glucose homeostasis in skeletal muscle-specific PGC-1α knockout mice reveals skeletal muscle-pancreatic β cell crosstalk. J. Clin. Invest. 117, 3463–3474 (2007).
Mootha, V. K. et al. PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nature Genet. 34, 267–273 (2003).
Patti, M. E. et al. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1. Proc. Natl Acad. Sci. USA 100, 8466–8471 (2003).
Alexandraki, K. et al. Inflammatory process in type 2 diabetes: The role of cytokines. Ann. NY Acad. Sci. 1084, 89–117 (2006).
St-Pierre, J. et al. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell 127, 397–408 (2006).
Valle, I. et al. PGC-1α regulates the mitochondrial antioxidant defense system in vascular endothelial cells. Cardiovasc. Res. 66, 562–573 (2005).
Moylan, J. S. & Reid, M. B. Oxidative stress, chronic disease, and muscle wasting. Muscle Nerve 35, 411–429 (2007).
Ji, L. L. Modulation of skeletal muscle antioxidant defense by exercise: Role of redox signaling. Free Radic. Biol. Med. 44, 142–152 (2008).
Brown, W. J., Burton, N. W. & Rowan, P. J. Updating the evidence on physical activity and health in women. Am. J. Prev. Med. 33, 404–411 (2007).
Perusse, L. & Bouchard, C. Genotype-environment interaction in human obesity. Nutr. Rev. 57, S31–38 (1999).
Rippe, J. M. & Hess, S. The role of physical activity in the prevention and management of obesity. J. Am. Diet. Assoc. 98, S31–38 (1998).
Hotamisligil, G. S. & Spiegelman, B. M. Tumor necrosis factor α: a key component of the obesity-diabetes link. Diabetes 43, 1271–1278 (1994).
Hotamisligil, G. S., Shargill, N. S. & Spiegelman, B. M. Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance. Science 259, 87–91 (1993).
Hamilton, M. T., Hamilton, D. G. & Zderic, T. W. Role of low energy expenditure and sitting in obesity, metabolic syndrome, type 2 diabetes, and cardiovascular disease. Diabetes 56, 2655–2667 (2007).
Fraser, G. E. & Shavlik, D. J. Ten years of life: Is it a matter of choice? Arch. Intern. Med. 161, 1645–1652 (2001).
Arany, Z. et al. The transcriptional coactivator PGC-1β drives the formation of oxidative type IIX fibers in skeletal muscle. Cell Metab. 5, 35–46 (2007).
Wagner, B. K. et al. Large-scale chemical dissection of mitochondrial function. Nature Biotechnol. 26, 343–351 (2008).
Arany, Z. et al. Gene expression-based screening identifies microtubule inhibitors as inducers of PGC-1α and oxidative phosphorylation. Proc. Natl Acad. Sci. USA 105, 4721–4726 (2008).
Handschin, C. & Mootha, V. K. Estrogen-related receptor α (ERRα): a novel target in type 2 diabetes. Drug Discov. Today Ther. Strateg. 2, 151–156 (2005).
We thank E. Smith for assistance with graphics. We also thank our colleagues and the members of our laboratories for comments on the manuscript, in particular S. Loffredo, J. Estall, Z. Arany, G. Hansson, S. Summermatter, M. Toigo and U. A. Meyer. C.H. is supported by the University Research Priority Program 'Integrative Human Physiology' of the University of Zurich, an SNSF-Professorship of the Swiss National Science Foundation and the Muscular Dystrophy Association. B.M.S. is supported by several grants from the National Institutes of Health.
The authors declare no competing financial interests.
Reprints and permissions information is available at http://www.nature.com/reprints.
Correspondence should be addressed to the authors (firstname.lastname@example.org; email@example.com).
About this article
Cite this article
Handschin, C., Spiegelman, B. The role of exercise and PGC1α in inflammation and chronic disease. Nature 454, 463–469 (2008). https://doi.org/10.1038/nature07206
Sports Medicine and Health Science (2020)
Laboratory Animal Research (2020)
Effects of Irisin Compared with Exercise on Specific Metabolic and Obesity Parameters in Female Mice with Obesity
Metabolic Syndrome and Related Disorders (2020)
Journal of Sport and Health Science (2020)
Pharmacological Research (2020)