I recently read a small blurb in Men’s Health Magazine about how exercise can actually change the expression of your genes, and considering that I am a geneticist at heart, I was skeptical and wildly curious at the same time. Usually, we think that our genes play a part in determining our body composition, and there’s nothing we can do about it. Some people are programmed to be thicker, some are programmed to gain muscle, some are programmed to eat whatever they want and stay thin (jerks). The idea that we can physically change our genetics by exercising is a new thought that would not only change the way we look at our bodies, but also take away that famed “It’s my genetics” excuse. This is the most research I have ever done for a post, mostly because it is a very new topic (3-4 years old), and because it is holy WOW interesting. So get ready, we’re goin’ in deep.
Let’s take a quick sec to delve into how the expression of genes can change without changing the actual code. Two of the most common yet most subtle methods of gene expression change are adding methyl groups to DNA nucleotides, aka DNA methylation, and adjustment of acetyl groups of the histones in the genes which are bundled tightly inside the DNA molecule. The acetyl groups are removed or added by enzymes called histone deacetylases or HDAC. The evolutionary purpose of DNA methylation was to make sure our embryonic stem cells differentiated into the proper type of cells, and never adjusted to become anything else. This is the reason why you don’t have a liver on your head and we have fingers instead of two long fin-like appendages. DNA methylation signaled to the cells between your fingers to differentiate into skin, and divide at a slower rate (1, 2). No one wants webbed fingers. Except maybe swimmers. But anyway… DNA methylation and HDAC are considered subtle changes because the actual genetic code is not changed. Methyl groups just alter the expression. Removal or addition of an acetyl group does not change the code. These types of expression changes, which can be inherited by offspring is called an “epigenetic” change (3). Causes of DNA methylation and HDAC are varied, but mostly thought to be environmental. Many of these environmental stimuli cause DNA methylation that leads to various types of cancer. Remember how the skin cells between your fingers stop dividing because you aren’t supposed to have webbed hands? That mechanism can be easily reversed to where the cells don’t know when to stop dividing. This forms a tumor (4).
But enough with the heavy. How can we manipulate this DNA methylation process in our favor? Basically, by doing what we already inherently know to be healthy. Eat well, and exercise.
In recent studies, obesity has been linked to epigenetic changes (5), because DNA methylation causes a silencing of important metabolic genes. This also leads to many cases of type II diabetes which is the area where most of the research on DNA methylation and HDAC is conducted.
So let’s get more specific. GLUT4 is a gene that regulates glucose uptake by muscles. Glucose uptake = very good thing. It means our muscles are burning energy (6). GLUT4 expression undergoes suppression by the regulatory gene MEF2, particularly when we are resting and conserving energy. MEF2 works by interacting with HDAC5 in histones of skeletal muscle DNA, and removes acetyl groups from GLUT4. Exercise causes MEF2 to dissociate from HDAC5, re-acetylate GLUT4 and uptake of glucose. Any method of removing glucose from the blood stream is treatment for type II diabetes (7). If you want more detailed information about this exercise effect, read this review article: http://diabetes.diabetesjournals.org/content/58/12/2718.full?ijkey=00c6022076d8a704bcdcb9685d64e0aca1355ec8&keytype2=tf_ipsecsha#ref-46
There have been two studies in the past year that have used 6 month exercise interventions on human subjects to explore the status changes of DNA methylation. In a 2012 study, the researchers had a cohort of 28 healthy men split into two groups. One group had a close family history (FH) of type II diabetes (T2D), and the other had no FH of T2D. The researchers measured the methylation of selected metabolism and insulin regulation genes. 134 genes changed in the men regardless of FH status. Just to be clear, it doesn’t necessarily matter if the DNA methylation increases or decreases as long as there is a change. DNA methylation is not well understood, so increases or decreases can invoke positive or negative changes physiologically. The researchers in this study chose to investigate one gene of the respiratory chain, NDUFC2. In this gene the DNA methylation decreased in all the men, moreso in those who had a FH of T2D. The researchers attempted to determine the physical and functional changes that resulted. In examining muscle tissue, the density of the mitochondria increased as did the lipid content of the mitochondria after exercise. This means that the muscles were making more mitochondria in order to increase the metabolism of energy. This is not only good news for diabetics, but for anyone who is obese. An increase in lipid concentration means that the mitochondria were getting to the fat stores, as well (8).
The 2013 study was conducted upon adipose tissue of 23 healthy men with a history of low physical activity, before and after a 6-month exercise intervention. Eighteen genes associated with obesity and 21 genes associated with T2D showed changes in DNA methylation. One important discovery was the increase in DNA methylation of the gene ITPR2, which has been loosely associated with waist-hip ratio (9). Another change in methylation occurred at the gene KCNQ1, which codes for a calcium channel that feeds forward the development of T2D. Changes in methylation in this gene are known to be highly heritable (10). DNA methylation also changed at 6 different sites in the TCF7L2 gene which is known for holding the most common risk factor for T2D (11). This study laid awesome ground-work for DNA methylation variants in human adipose tissue, but there is much more functional work to be done (12).
Now before you think to yourself, “What’s the big deal? I already knew that exercising was good for me,” think of it this way. Exercise changes us down to the little tiny carbons on our DNA. And not just in our muscles, but in our fat stores, as well. Exercise could be changing the methylation of the DNA in our brains, our nerves, anywhere, but the research hasn’t gotten that far. The point I’m trying to make is that exercise really could give you a better life. It’s not just about looking better. Also, some of these changes in DNA methylation can be passed on to your offspring. Do you want to pass on to them DNA with a crazy-bad methylation profile? Your good/bad choices can affect offspring. Another take home point is that this discovery could lead to more targeted treatments for those who already have diseases influenced by methylation and HDAC.
1. Iqbal, K.; Jin, S. -G.; Pfeifer, G. P.; Szabo, P. E. (2011). “Reprogramming of the paternal genome upon fertilization involves genome-wide oxidation of 5-methylcytosine”. Proceedings of the National Academy of Sciences 108 (9): 3642–3647.
2. Wossidlo, M.; Nakamura, T.; Lepikhov, K.; Marques, C. J.; Zakhartchenko, V.; Boiani, M.; Arand, J.; Nakano, T.; Reik, W.;Walter, J. R. (2011). “5-Hydroxymethylcytosine in the mammalian zygote is linked with epigenetic reprogramming”. Nature Communications 2: 241.
4. Wong NC, Craig JM (2011). Epigenetics: A Reference Manual. Norfolk, England: Caister Academic Press.
5. Tateishi K, Okada Y, Kallin EM, Zhang Y: Role of Jhdm2a in regulating metabolic gene expression and obesity resistance. Nature2009; 458: 757– 761
6. Neufer PD, Dohm GL: Exercise induces a transient increase in transcription of the GLUT-4 gene in skeletal muscle. Am J Physiol1993; 265: C1597– C1603
7. McGee SL, Hargreaves M : Exercise and skeletal muscle glucose transporter 4 expression: molecular mechanisms. Clin Exp Pharmacol Physiol 2006; 33: 395– 399
8. Marloes Dekker Nitert, Tasnim Dayeh, Peter Volkov, Targ Elgzyri,Elin Hall, Emma Nilsson, Beatrice T. Yang, Stefan Lang,Hemang Parikh, Ylva Wessman, Holger Weishaupt, Joanne Attema, Mia Abels, Nils Wierup, Peter Almgren,Per-Anders Jansson Tina Rönn, Ola Hansson,Karl-Fredrik Eriksson, Leif Groop, Charlotte Ling. Impact of an Exercise Intervention on DNA Methylation in Skeletal Muscle From First-Degree Relatives of Patients With Type 2 Diabetes. Diabetes December 2012vol. 61 no. 12 3322-3332.
9. Heid IM, Jackson AU, Randall JC, Winkler TW, Qi L, et al. (2010) Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. Nat Genet 42: 949–960.
10. Travers ME, Mackay DJ, Nitert MD, Morris AP, Lindgren CM, et al. (2012) Insights Into the Molecular Mechanism for Type 2 Diabetes Susceptibility at the KCNQ1 Locus From Temporal Changes in Imprinting Status in Human Islets. Diabetes 62: 987–92.
11. McCarthy MI (2010) Genomics, type 2 diabetes, and obesity. N Engl J Med 363: 2339–2350
12. Tina Rönn, Petr Volkov, Cajsa Davegårdh, Tasnim Dayeh, Elin Hall, Anders H. Olsson, Emma Nilsson, Åsa Tornberg, Marloes Dekker Nitert, Karl-Fredrik Eriksson, Helena A. Jones, Leif Groop, Charlotte Ling. A Six Months Exercise Intervention Influences the Genome-wide DNA Methylation Pattern in Human Adipose Tissue. Department of Clinical Sciences, Epigenetics and Diabetes, Lund University Diabetes Centre, CRC, Malmö, Sweden. email@example.com.