Research Blog

Winding Up Your Body's Clock

clock of circadian rhythm

Scheduled physical activity is found to help regulate and amplify the body's circadian rhythm. This suggests a way for curing defective circadian rhythms and a multitude of diseases that have been linked to malfunctioning circadian rhythms. 

Animals, including humans, utilize clocks called circadian rhythms to keep the body aligned with nature's daily night and day cycle. The circadian rhythm is controlled by the suprachiasmatic nucleus in the brain. The circadian rhythm is a daily cycle of behavioral and physiological functions regulated by fluctuating levels of hormones. Malfunctions in the circadian rhythm often develop in the elderly and a recent study found these malfunctions in the circadian rhythm may be to blame for a myriad of diseases including diabetes, cancer, cardiovascular disease and mood disorders [Arendt J (2010). Occup Med (Lond) 60, 10–20.]. A study published in the December 2012 Journal of Applied Physiology found that scheduled physical activity strengthens and regulates the circadian rhythm (Voluntary scheduled exercise alters diurnal rhythms of behavior, physiology and gene expression in wild-type and vasoactive intestinal peptide-deficient mice, 2012. Analyne M. Schroeder, et al.). 

In the study mice were given varying levels of access to a running wheel: no access, free access, late night access and early night access. By measuring ambulatory activity, body temperature, heart rate and circadian rhythm hormones the researchers found that having scheduled access had a strong control over their circadian rhythm. Even free access versus no access had an effect. Mice are naturally active at night. The figure below shows how varying access to running wheels affected their ambulatory activity.

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Ambulatory activity in wild-type mice as a function of time of day in response to no, free, early night and late night access to running wheels.

Even more interesting was the effect of the running wheel access variable in vasointestinal polypeptide (VIP) deficient mice. VIP deficiency leads to circadian rhythm loss of function. Late night running wheel access was able to restore many of circadian physiological and behavior cycles to those seen in the wild type (VIP normal) mice. One of the molecular clocks measured was PER2 and Luciferase, the ratio of which corresponds to different points in the circadian rhythm. The figure below compares this molecular clock with wild type mice.

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A measurement of PER2::Luc ratios in VIP deficient mice (VIP -/-) as a result of varying access to a running wheel. The dotted lines represent the levels seen in the wild-type mice.

What this study shows is that not only can exercise be important for therapy, but the time that exercise is performed is also important. For people who perform exercise on a daily basis, maintaining a standard workout schedule is beneficial because our bodies are "ready to go"at the workout time each day. Apparently, this readiness does not require our normal circadian rhythm machinery as evident by the VIP deficient mice's ability to get on a schedule. Further research is needed to show that scheduled physical activity can help elderly patients suffering from a loss of circadian rhythm function.

Resistance Training vs Aerobic Training for Weight Loss

resistance training newport beach

A large study finds that resistance training is not as effective for reducing body weight as aerobic training.

A recent study conducted by researchers at Duke University looked at the weight loss efficiency of aerobic training, resistance training and a combination of the two (Effects of aerobic and/or resistance training on body mass and fat mass in overweight or obese adults, 2012. Leslie Willis, et al.). As expected, the study found that the training strategies have very different affects on the body.

Resistance training involves any type of exercise where the joint performs a full motion with a force opposed to that motion. With elastic bands the opposing force increases as the motion is extended. In hydraulic resistance training the opposing force increases as the speed of motion increases.  Aerobic training includes repetitive motions such as cycling, swimming and running. For this particular study weight lifting was used for resistance training. A cycling machine, elliptical machine and treadmill were used for the aerobic training.

Those subjects participating strictly in resistance training saw no decrease in body mass. However, this was because any decrease in fat was offset by an increase in  lean body mass. The fat composition was reduced by resistance training participants. On the other hand, aerobic training participants saw a significant drop in both fat composition and total body mass. When time is considered, the aerobic training is even more efficient. Aerobic training in this study took 133 minutes a week compared to the 180 minutes a week spent by the resistance training group.

The effect of different modes of exercise on change in body mass and body composition.  ††P < 0.05, †P < 0.10 Post Hoc Test compared with resistance training. ‡‡P < 0.05 Post Hoc Test compared with aerobic training.

Interestingly, no increase in weight loss was observed when resistance training was added to aerobic training, but there was a significant drop in fat percent.  Waist circumference has been found by some studies to be a better predictor of cardiovascular health than BMI. Although resistance training by itself did not decrease waist circumference, it created a significant drop when added to aerobic training relative to aerobic training by itself.

In conclusion, despite what resistance bands manufacturers or resellers claim, resistance training does not burn fat or decrease body weight according to this study. From this study it appears that the best method of losing fat is aerobic training. If time allows, resistance training can be added on.

Working out alters DNA


Exercise is found to alter the methylation of cell metabolism related promoter regions in human subjects.

DNA expression is a complicated process that has yet to be completely unraveled by geneticists. One way DNA expression is regulated is through methylation. Methylation involves attachment of methyl groups (-CH3) to the DNA, inhibiting its expression. When a promoter region becomes heavily methylated expression of the corresponding gene becomes inhibited.  Methylation plays a role in cell differentiation; specialized cells are methylated in characteristic patterns. Geneticists previously believed that methylation is permanent within an adult cell. However, a recent study first published in Cell Metabolism and featured in Nature found that exercise alters methylation (Acute Exercise Remodels Promoter Methylation in Human Skeletal Muscle, 2012. Romain Barres, et al.).

Exercise was found to demethylate cell metabolism promoter regions in sedentary men and women following acute exercise. In the study muscle biopsies were performed on the subjects following acute exercise at 40% and 80% of maximum. The figure below shows that methylation was significantly reduced in the muscle after acute exercise. In addition, promoters for genes involved in energy metabolism where analyzed in muscle fibers. The figure shows that for all the energy metabolism genes (PGC-1a, TFAM, PPAR, CS and PDK4) methylation was found to be reduced in their respective promoters.  This was not the case for muscle specific genes MEF2A and MYOD1 as well as the muscle "housekeeping" gene GAPDH.

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Acute Exercise Remodels DNA Methylation: (A) Global CpG methylation analysis at rest (REST) and 20 minutes after acute exercise (ACUTE EXERCISE). (B) Ratio of methylation after acute exercise and at rest, dashed line represents no change. *p<0.05, **p<0.01

Similar changes in gene expression were observed following exercise. Exercise increased the gene expression of the demethylated genes as measured by mRNA levels. The intensity of exercise affected the significance of demethylation. Working out at 40% of maximum effort produced less of an effect than at 80% of maximum effort. Within three hours of the exercise effort most of the demethylation effect observed immediately post exercise session had disappeared. Isolated mouse soleus were observed to determine whether exercise-induced factors were needed to cause the methylation changes seen in the human subjects. The mouse muscle fibers contracted ex vivo showed methylation changes as shown by the figure below. This means that external factors are not needed to change the methylation, but the contracting fiber itself causes the changes. Gene expression peaked three hours after the ex vivo muscle contractions. Meanwhile, hypomethylation occurred 45 minutes after ex vivo muscle contractions.

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Muscle Contraction Induces Hypomethylation: Gene expression (A) and promoter methylation (B) in isolated mouse soleus. *P<0.05

The study also found that large doses of caffeine induced hypomethylation. The mechanism, the authors believe, is through caffeine-induced calcium release from sarcoplasmic reticulum (the cause of contraction according to the sliding-filament theory). Because the gene expression and methylation patterns differed slightly, gene expression is influenced, but not completely controlled by, DNA methylation.

This study has ramifications beyond exercise. This introduces the novel concept that the environment can influence DNA methylation in non-dividing, somatic, adult cells. Epigenetic marks across the genome are subject to greater disparity than formerly realized.

Examining the Controversy: Is too much exercise bad for the heart?

swimming in triathlon

The mainstream media claims from recent research vigorous exercise is unhealthy.  That isn't the complete picture.

Over the past several months a flurry of studies suggesting too much exercise is detrimental to one's health has sparked fierce debate over the legitimacy of the claims. The mainstream media has jumped into the fray. The Wall Street Journal published an article "One Running Shoe in the Grave" arguing too much exercise stresses the heart enough to erase any physical activity health gains. What did the studies actually find, and is it a cause for concern?

One study tracking 52,000 adults for 15 years found that runners had a 19% decrease in all-cause mortality. However, when it was broken down by mileage a U-shaped curve emerged. Those exercising moderately for 2-5 days a week had the lowest mortality. The extremes had the highest mortality. In fact, the people running more than 25 miles a week had almost as high a mortality rate as those not exercising at all. The figure below shows this "U-curve" from the study (Running and all-cause mortality risk: is more better? 2012. Lee J, et al.)

However this does not give the complete picture. Another study, published in 2011, found that vigorous exercise and moderate exercise had differing amounts of benefit towards reducing mortality risk. The authors found that moderate exercise showed a gentle, increasing curve when plotted against mortality risk.  Meanwhile, vigorous exercise had far higher marginal returns up to about 50-60 minutes a week when it began to plateau. For both vigorous and moderate exercise, diminishing returns was observed as expected. However, no negative relationship was seen with extreme durations of daily exercise. The relationship can be seen in the figure below (Minimum amount of physical activity for reduced mortality and extended life expectancy: a prospective cohort study, 2011. Wen CP, et al.) 

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So although the relationship cannot be fully established, if vigorous exercise does cause an increase in mortality risk past a certain point what is the cause?  According to a review by cardiologist James O'Keefe and colleagues, the cause is a problem with heart function.  (Potential Adverse Cardiovascular Effects From Excessive Endurance and Exercise, 2012.  James O'Keefe, et al.). Athletes develop an enlarged left ventricle to enable increased circulation. This remodeling does not disappear for at least several years following retirement from vigorous exercise. Several biomarkers for myocardial damage appear to be elevated following intense, prolonged races such as triathlons or marathons.  Myocardial scarring from vigorous exercise may lead to problems. Endurance athletes have been shown to have a higher rate of electrocardiogram problems.  Endurance athletes may have a five-fold increase in prevalence of atrial fibrillation. The increase in atrial size from endurance training may be responsible for atrial fibrillation.

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Other problems with the cardiovascular system that show up in endurance athletes include coronary artery calcification, diastolic dysfunction, aorta wall stiffening and myocardial fibrosis. Despite all these potential problems the authors add that lifelong vigorous exercisers generally have low mortality and great cardiovascular function; its an interesting paradox.

In conclusion, if health is your sole reason for exercising it may be best to limit exercise to 2-5 days a week of moderate exercise. However, the risks of vigorous exercise are highly speculative until more research comes out. The mainstream media is likely exaggerating the findings of recent studies or drawing hypothetical conclusions. When carefully looking at the data and the papers collectively, the research says vigorous exercise is still good for the body. Regardless of which side ultimately wins the debate, exercise is undoubtedly good for the mind and collective well-being.

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