Research Blog

scientist doctor conducting medical or biological research

The Research Blog at Exercise Medicine is the place to discover the latest research on exercise and healthy living from the medical field. Within this blog are tips for the athlete seeking a competitive advantage, information for the patient looking to live healthier and research for the doctor searching for novel treatment ideas. Enjoy!

If you enjoy this blog be sure to contribute your own thoughts and research by sending an email to contact@exercisemed.org, posting on this site’s Facebook page or leaving a comment below.

Aerobic Exercise for Fibromyalgia

fibromyalgia


Individuals suffering from fibromyalgia will benefit from exercise.





Fibromyalgia classically presents in young to middle-aged women with fatigue, widespread musculoskeletal pain and mood disturbances such as depression. It is a chronic noninflammatory condition thought to be related to abnormal pain processing in the nervous system. Unlike polymyalgia rheumatica, which is an autoimmune disease with similar features of widespread muscle and joint pain, there are no signs of increased inflammation in fibromyalgia. Therefore, taking anti-inflammatories such as NSAIDS (i.e. aspirin or ibuprofen) or steroids are not first line pharmaceutical treatments for fibromyalgia. Instead, antidepressants are often used as a pharmaceutical treatment because fibromyalgia is primarily a nervous system disorder. An even better treatment than antidepressants is exercise. 

The effectiveness of exercise in treating fibromyalgia has been known for decades. The first clues came from a study done in the 1970s in which college students were startled awake in the middle of sleep. Many of the participants began to develop diffuse body aches similar to those experienced with fibromyalgia. However, the investigators noted that the elite runners participating in the study did not suffer these adverse symptoms. In 1994, a clinical trial looked at 99 women with fibromyalgia who were treated with physical training (A randomized, controlled clinical trial of education and physical training for women with fibromyalgia, 1994. Buckhardt, et al.). The clinical trial found that physical training improved patients quality of life and self-efficacy. Six weeks in physical training resulted in significant decreases in helplessness, the number of days feeling bad, physical dysfunction, and pain at tender points. 87% of patients in the physical training group were exercising three times or more per a week.

swimming

Studies have looked at a variety of different types of exercise. Aerobic exercise and mixed modality exercise appears to be the most potent treatment for fibromyalgia. Strength training, resistance work outs and even flexibility exercises have also been shown to be effective in combating fibromyalgia (Exercise interventions in Fibromyalgia: Clinical applications from the Evidence, 2009. Jones KD and Liptan GL). In terms of the specific type of aerobic exercise, research has not been able to dissect a difference between various types of aerobic exercise. A recent study out of Brazil compared the effectiveness of walking and swimming, both aerobic types of exercise, and found both were effective means of alleviating fibromyalgia pain. Both walking and swimming helped individuals with fibromyalgia improve functional capacity and raise quality of life (Swimming Improves Pain and Functional Capacity of Patients with Fibromyalgia: A Randomized Controlled Trial, 2016. Fernandes, et al.). In addition to exercise, improved sleep hygeine can play a role at eliminating fibromyalgia symptoms.

Beyond fibromyalgia, exercise can help patients wth chronic pain syndromes improve their physical capacity. A paper from Cochrane Reviews analyzed 21 reviews with 381 studies totaling 37,143 participants to determine the effect of exercise on chronic pain (Physical activity and exercise for chronic pain in adults: an overview of Cochrane Reviews, 2017. Geneen, et al.). The conclusion was that exercise can improve physical function in these patients with a minimal benefit toward alleviating the chronic pain. There were few adverse effects of exercise, the authors concluded, another reason to try exercise before starting pharmaceutical treatments when attempting to get rid of chronic pain.

Exercise Helps the Immune System Fight Cancer

Tumor attacked by white blood cell


A study finds that the adrenaline or epinephrine released with exercise enhances NK cell mobilization to tumorous growths. NK cells are a critical component of the innate immune system that function to kill cancerous cells and virally infected cells.



We have previously explored how exercise can weaken the immune system. Open window theory states that the immune system is weakened 3-72 hours after a bout of intense endurance exercise due to a skeletal muscle inflammation mediated disruption in cytokine levels. Cytokines are small signaling molecules that guide inflammatory cells to areas of infection or damage. Immune system dysfunction probably explains the increased susceptibility to infectious disease seen in athletes after a intense bout of exercise. Although intense exercise may increase one’s susceptibility to infection, research suggests that exercise boosts the body’s ability to fight cancer.

Epidemiological studies have previously noted that exercise protects individuals  from cancer, in addition to well-known chronic diseases like obesity, diabetes and coronary heart disease. Recent evidence suggests that the immune system plays a vital role in exercise’s ability to help fight off cancer.

A novel study published in the March 2016 issue of Cell Metabolism has been garnering interest because it demonstrated that epinephrine, IL-6, and Natural Killer cells all play an integral part in reducing tumors in exercised mice. Epinephrine, more commonly referred to as adrenaline, is an important signal molecule that allows the sympathetic nervous system to alert the body of a “fight or flight” response. Epinephrine ramps up the heart rate, reduces gut activity by constricting intestinal blood flow and increases blood flow to skeletal muscle. These actions make epinephrine an important signaling molecule during exercise (and explains why patient’s on beta-blockers, an anti-hypertension medication, have reduced maximal exercise capacity). IL-6 is a cytokine, or immune signaling molecule, that induces fever and stimulates the production of additional immune system proteins called acute phase reactants. Natural killer cells are a special innate immune system cell that destroys the body’s own cells when they are damaged by viral infection or have become cancerous by using special cytotoxic ("cell-killing”) proteins called perforin and granzyme.

The aforementioned study found that mice with running wheels for voluntary exercise had reduced tumor incidence and growth (Voluntary Running Suppresses Tumor Growth through Epinephrine and IL-6 Dependent NK Cell Mobilization and Redistribution, 2012. Pedersen, et al.). Interestingly, this effect was found to hold up for different tumor models (i.e. melanoma, etc.) and anatomical locations. 

Mice were injected with a carcinogenic toxin called diethylnitosamine, which induces tumors within 10 months in mice. Mice were housed with running wheels or without running wheels. Although 31% of running mice developed tumors, 75% of the control mice developed tumors. In addition, the tumors in running mice were smaller by volume and weight. This finding is shown in the figure below.

Bar graph showing tumor volume is reduced in exercised mice. Average tumor volume (mm3) in mice housed with running wheels (EX, n=12) and without running wheels (CON, n=11). Subcutaneous B16F10 tumors in C57BL/6 mice. *p<0.05, Students T-test

What was mediating the difference in tumor burden between running and control mice? The running mice had increased Natural Killer (NK) cells in their tumors. Recall that NK cells destroy cancerous cells. In fact, control mice had barely detectable levels of NK cells in their tumors. The NK cells in both mice groups had similar cell killing ability. The researchers discovered epinephrine (adrenaline) to be implicated in the NK cell recruitment. Blocking epinephrine with the anti-hypertensive medication propanol during exercise led to a blunted exercise anti-tumor effect. Perhaps most interesting was that an injection of epinephrine in control, non-running mice led to a reduction in tumor burden that was nearly as large as the reduced burden seen in running mice. 

IL-6 is an interleukin, or immune system signaling molecule, that was also implicated in mediating the exercise-induced inhibition of tumor growth. Blocking IL-6 using an antibody negated the exercised-induced reduction in tumor burden. However, unlike epinephrine, an IL-6 injection independent of running had no effect on tumor burden in non-running control mice. In addition, other pro-inflammatory cytokines such as IL-1 and iNOS were found to be up-regulated in the tumors of running mice relative to control mice.

Proposed mechanism that voluntary running in mice suppresses tumor growth. Exercise mobilizes NK cells via epinephrine and IL-6 to redistribute to tumors. NK cells are immune cells that then destroy the cancerous cells that compose the tumor. Epinephrine, also known as adrenaline, is produced during exercise. IL-6 is an immune system signaling molecule.

Therefore, running or exercise in general may reduce cancer incidence by increasing NK cell mobilization to cancerous cells. It appears this phenomenon is mediated by epinephrine and immune cytokines such as IL-6. That an epinephrine injection is able to reduce tumor incidence in mice, raises the exciting prospect that an epinephrine injection could be utilized to help fight cancer in patients who are unable or unwilling to exercise. Epinephrine injections are currently used to raise blood pressure in individuals whose are dangerously hypotensive, such as via an anaphylactic reaction to a bee sting. However, it also raises the question to what extent do beta-blockers increase tumor incidence by eliminating the anti-cancer benefits of epinephrine. Of course, the benefits and adverse events seen in mice models may not extrapolate to humans. More research will be necessary to fully understand the anti-cancer immunological benefits of exercise in humans, and whether there are practical lifestyle or pharmaceutical therapeutics to be gained from this research.

In conclusion, running mice were found to have significantly reduced incidence of tumors relative to non-running controls apparently via a NK cell and epinephrine immunological mechanism. This raises the tantalizing prospect of adding epinephrine and exercise to our arsenal of weapons to battle cancer.

Estrogen’s Critical Role in Muscle Insulin Sensitivity and Preventing Metabolic Syndrome

breast carcinoma tissue stained for estrogen receptor




The estrogen receptor plays an important role in maintaining the health of skeletal muscle mitochondria. This process attenuates insulin resistance. Insulin resistance leads to a downstream cascade towards metabolic syndrome and diabetes mellitus. On the right is a breast carcinoma tissue stained for estrogen receptor.


Estrogen is well known to play a protective role against a variety of diseases. Estrogen maintains bone health preventing osteoporosis, protects against metabolic syndrome and likely plays a role vascular health, decreasing the risk of cardiovascular disease. These physiologic effects led estrogen to be deemed the youth hormone. For decades, postmenopausal women were prescribed estrogen to maintain bone health and prevent cardiovascular disease. However, this practice, commonly called hormone replacement therapy (HRT), fell out of favor in 2002 when new studies showed all-cause mortality was actually higher in postmenopausal women on HRT. A recent study published in Science Translational Medicine sheds light on an additional organ system that estrogen acts on: skeletal muscle. This study found that the estrogen receptor is essential for maintaining skeletal muscle mitochondria with the downstream consequences of increased reactive oxygen species clearance and insulin sensitivity-loss of which plays an essential role in the pathogenesis of type II diabetes mellitus (Skeletal muscle action of estrogen receptor α is critical for the maintenance of mitochondrial function and metabolic homeostasis in females, 2016. Ribas, et al.).

Skeletal muscle plays an important part in the regulation of blood glucose levels. In response to insulin, skeletal muscle takes up glucose via GLUT4 channels. When the skeletal muscle becomes unresponsive to insulin (insulin insensitivity) the muscle fails to take up glucose from the blood resulting in the elevated blood glucose levels characteristic of diabetes. Metabolic syndrome is a precursor to diabetes mellitus and includes elevated LDL cholesterol, central obesity, reduced glucose tolerance and high blood pressure.

Mitochondria are the powerhouses of most cells in the body (red blood cells being the notable exception). These organelles generate energy for the cell in the form of ATP. In any cell, damage to mitochondria can result in reactive oxygen species and possibly irreversible cell damage. Mature skeletal muscle cells do not replicate and rely on healthy mitochondria to supply their aerobic energy demands. Although muscle fibers do not replicate during our adult lives, their mitochondria must replicate to avoid damage over the myofiber lifespan. With this background on mitochondria, skeletal muscle and metabolic syndrome lets investigate the role of estrogen.

Muscle estrogen receptor expression is lower in women with metabolic syndrome

In the aforementioned study, premenopausal women with metabolic syndrome were found to have lower levels of skeletal muscle estrogen receptors. This finding of reduced skeletal muscle estrogen receptors was also found in obese mice. The findings in postmenopasaul women are shown in the figure to the right. The next step for the researchers was to determine the mechanism responsible for linking metabolic syndrome to low skeletal muscle estrogen receptor levels.

The researchers selectively knocked out the estrogen receptor from skeletal muscle in mice to investigate the mechanism by which low estrogen receptors in skeletal muscle are associated with metabolic syndrome. They called these skeletal muscle estrogen receptor deficient mice MERKO (Muscle Estrogen Receptor Knock Out) mice. MERKO mice demonstrated a smorgasbord of health problems including decreased glucose tolerance and a depressed muscle insulin response. Recall that insulin resistance plays an essential role in the pathogenesis of diabetes by impairing glucose uptake into skeletal muscle when blood blood glucose levels are elevated (i.e. after a meal). In addition, MERKO mice displayed increased muscle inflammation and higher levels of lipids or fat in the muscle. Muscle endurance was diminished in mice without a skeletal muscle estrogen receptor, although peak tension remained the same.

Muscle mitochondrial damage in the MERKO mice suggests that estrogen may play an important role in maintaining muscle mitochondria health. Mitochondria function was reduced as measured with several tests including cellular oxidative capacity, reactive oxygen species (ROS) scavenging capacity and calcium handling. Furthermore, damage to the mitochondria in MERKO mice led to higher levels of free radicals in the muscle cells of MERKO mice.

mitochondrial DNA replication is reduced in muscle lacking estrogen receptor resulting in altered mitochondrial morphology.

Apparently, skeletal muscle estrogen receptors are necessary for smooth mitochondrial DNA (mtDNA) replication during mitochondrial turnover. Although most DNA in humans, or any eukaryotic organism for that matter, is stored in the nucleus, the mitochondria retains a small genome that produces proteins necessary for mitochondrial function. Increased mitochondrial DNA mutations and decreased mtDNA replication resulted in muscle mitochondria with altered morphology. The mitochondria shape and size discrepancy between normal (Control) and muslce estrogen receptor deficient (MERKO) mice can be seen in the electron microscope images of mouse muscle above.

Impaired mitochondria in skeletal muscle does not directly explain why these estrogen receptor deficient myofibrils exhibited impaired insulin sensitivity. Interestingly, the researchers identified a known oxidative stress response gene that was up regulated in the estrogen deficient mouse muscle cells. The gene, Rcan1, is a known inhibitor of the protein phosphatase calcineurin. Calcineurin activity is important for mitochondria fission and autophagy. Rcan1 also directly increases a DNA polymerase for mtDNA replication. Besides impairing mitochondria, Rcan1 decreases insulin sensitivity through its inhibitory action on calcineurin. Confirming its importance in the muscle estrogen receptor deficient pathogenesis of metabolic syndrome, Rcan1 levels were increased in the skeletal muscle of premenopausal women with metabolic syndrome. 

As an aside, calcineurin is a common immunosuppression target. Prograf (tacrolimus) and Sandimmune or Neoral (cyclosporine) are calcineurin inhibitors commonly used for suppressing the immune system in organ transplant recipients and patients with autoimmune disease. A common adverse effect of these immunosuppressant drugs is, you guessed it, metabolic syndrome. Calcineurin inhibitor drugs are essentially synthetic versions of Rcan1.

In conclusion, it appears estrogen receptors play an important role in maintaining skeletal muscle longevity through their action on mitochondrial health and function. This is important because a deficiency of skeletal muscle estrogen receptors leads to muscle inflammation and impaired insulin action. Insulin resistance is an essential componeny in the pathogenesis of type II diabetes mellitus and helps mediate metabolic syndrome. Skeletal muscle estrogen receptors may represent a target for treating metabolic syndrome.

How did the Zika virus get to Brazil?

aides mosquito transmits the Zika virus



On the right is the Aedes mosquito, which is responsible for transmitting the Zika virus. How the Zika virus got to Brazil is still under investigation, but several hypotheses exist.







Many public health officials are concerned that the upcoming 2016 Summer Olympics in Brazil could write the recipe for a global Zika pandemic. While an athletic event may yet unleash Zika virus from Brazil to the rest of the world, it is also possible that an athletic event introduced Zika to Brazil. A genomic analysis of the Zika virus published in Science sheds some light on how the Zika virus got to Brazil and its relation to the 2013 outbreak in French Polynesia (Zika virus in the Americas: Early epidemiological and genetic findings, 2016. Nuno Rodrigues Faria, et al.).

Zika virus was detected in Brazil for the first time in May of 2015. However, microcephaly Zika-associated cases were not discovered until November 2015. It is possible that the Zika virus was introduced into Brazil a year before the first confirmed cases, putting the virus's entry date sometime in 2014. Genomic analysis showed that the Brazilian Zika virus ancestral origin is likely linked with the Zika virus epidemic in French Polynesia. Between late 2013 and early 2014 Zika hit an estimated 20,000 people in the southeastern Asian islands. No Zika-associated birth defects were found at the time, but respective analysis found a high level of birth defects during this period although the link was never proven. The Zika epidemic in French Polynesia ended quickly, after just a few months it was gone. There has not been a confirmed case of Zika since April 2014 in French Polynesia.

The Zika virus is hypothesized to have come to Brazil from the Pacific Islands during one of several athletic events held in Brazil during 2013 and 2014. These include the 2014 FIFA World Cup, the 2014 Va’a canoe event in Rio De Janeiro, and the 2013 FIFA Confederations Cup. Although the introduction of Zika could have occurred at any of these events, there was a nearly 50% increase in airline passengers arriving from South Pacific countries with prior Zika epidemics to Brazil throughout 2013. These athletic events all likely contributed to this increase in Brazil-bound airline passengers. Thus, it may be more important to look at overall travel patterns rather than any single athletic event to determine the spot of viral origin.


Hyponatremia: Its the water, stupid.

Boston marathon runner gets hydrated

Hyponatremia is a rare, but devasting consequence of hydrating too much without salt replacement. Fortunately, rehydrating right makes hyponatremia easy to prevent and can boost performance.




In 2005, a study published in the New England Journal of Medicine highlighted the prevalence of hyponatremia in marathon runners (Hyponatremia among Runners in the Boston Marathon, 2005. Christopher Almond, et al.). The study found that thirteen percent of Boston marathon finishers had hyponatremia and 0.6 percent of Boston marathon finishers had “critical" hyponatremia. They also found that slower runners had a higher prevalence of hyponatremia. However, at the Boston marathon slow is relative. Weight gain during the race (replenishing fluids faster than they are lost) was also a predictor of hyponatremia. So what is hyponatremia, and why is it harmful and even potentially fatal?

Hyponatremia is when sodium concentration in the blood drops below the normal physiological range. A physiological normal concentration of sodium is 135-145 meq/L, but during hyponatremia the sodium concentration can decrease to 130 meq/L and in severe cases can go below 120 meq/L. In athletes, this occurs when fluids, but not solutes, are replaced as they are lost in sweat. Sweat is hypoosomotic, meaning that it contains salt but at a lower concentration than what is found in the blood. A marathoner who sweats four liters of sweat with 40 meq/L of sodium loses about 160 meq of sodium. If the marathoner replaces the lost fluid with four liters of pure water, his or her sodium concentration will be significantly reduced.

So why is hyponatremia bad for us? The body relies on a fine balance of solutes between the cells and blood. If the solute concentrations are not balanced inside and outside our cells, fluid will flow down its concentration gradient and into or out of the cells in a process called osmosis. Furthermore, salt balance is essential for any organ that relies on salt gradients to maintain an electrical gradient and conduct electrical signals (i.e. the heart and brain, two very important organs!). The primary concern of hyponatremia is cerebral edema from water being sucked from the blood into neurons and other cells in the brain. This occurs because the dilute blood is sending water osmotically into the concentrated cells (acute hyponatremia leads to loss of solute in the blood and extracellular fluid, but not inside the cells). Because the brain cannot expand in the skull, intracranial pressure increases, similar to the effect of a intracerebral tumor or hydrocephalus.

At a hyponatremic serum sodium concentration of 125 to 130 meq/L, nausea and malaise may develop, which can be mistakenly attributed to the rigors of the physical exertion. As the serum sodium concentration drops below 120 meq/L, headache, lethargy, seizures, coma and respiratory arrest may ensue. The resulting encephalitis can lead to permanent brain damage.

The acute nature of hyponatremia seen in strenuous exercise prevents the brain from having a chance to adapt by reducing its intracellular osmolytes. To prevent the acute onset of hyponatremia seen in marathoners and other dehydrating athletic events, it is important to replenish lost sweat with both fluids and solutes. Gatorade or an alternative sports drink will do the trick. Another method is small salt tablets with your water (Based on your weight loss during an athletic event, its possible to predict the amount of salt lost in sweat. Rates vary from person to person, but on average about 500mg of salt is lost per pound of lost body weight due to sweating).

Hyponatremia is rare, but because the consequences are so severe and it is easily prevented it is good to be aware of it. Furthermore, one study found that dehydration is far more prevalent than hyponatremia in ultra-endurance athletes (The prevalence of exercise-associated hyponatremia in 24-hour ultra-mountain bikers, 24-hour ultra-runners and multi-stage ultra-mountain bikers in the Czech Republic, 2014. Daniela Chlibkova, et al.). Thus, it is important to stay hydrated, without overdoing it. As Christopher Almond and colleagues demonstrated, weight gain is a sign of hyponatremia. Weight gain likely means that one is drinking more fluids than were lost in sweat. Thus, they recommend using scales as a quick assessment of hyponatremia. In most cases that is not very practical.

For safe hydration, there are steps to take before a race or during an athletic event. It is important to be hydrated, but drinking too much before does not help. First, humans are not camels and therefore any extra water that the body sees goes straight to the bladder. Second, large quantities of water before a race or athletic event washes out the concentrating gradient in the kidney’s renal medulla. Losing the renal medulla concentration gradient actually inhibits one’s ability to concentrate urine and conserve water when they need it most!

In summary, to prevent hyponatremia and dehydration a comfortable amount of water will suffice beforehand. During and after the race or athletic event, it is important to replace salt lost in the sweat with Gatorade, other sports drinks or simply salt tablets with your water.

Exercise Is a Critical Component of COPD Rehabilitation

Netter depiction of a man with chronic bronchitis COPD.


Exercise training, along with smoking cessation, are key components for treating COPD and are an important piece of pulmonary rehabilitation.









Chronic Obstructive Pulmonary Disease (COPD) is the third leading cause of death in the United States. COPD is associated with chronic, progressive lung airflow limitation in response to noxious particles. In the US, 80-90% of COPD patients are smokers, but worldwide biomass fuel pollution is the most common etiology. In addition, a genetic defect in the protease inhibitor alpha-1 antitrypsin is responsible for 1-3% of cases of COPD.

Regardless of the trigger, COPD is caused by an uncontrolled or hyperactive immune response, which leads to emphysema and/or chronic bronchitis. COPD is defined by trouble with expiration, which leads to air trapping in lung alveoli and the classic presentation of a "barrel chest” in COPD patients. Although men previously had a higher incidence of COPD, today women have a higher COPD incidence and mortality rate than their male counterparts as a result of increased smoking rates among women. COPD patients generally feel short of breath (dyspnea) and this is exacerbated upon exertion.

There are several evidence-based guidelines for treating COPD to reduce morbidity and mortality. Smoking cessation is paramount and can lead to a dramatic halt in the progression of the disease. Along with smoking cessation, oxygen therapy, bronchodilators and surgery (lobectomy) are other proven measures of reducing COPD mortality. Pulmonary rehabilitation and vaccination are other measures proven to reduce COPD morbidity.

COPD Exercise-Dyspnea Spiral

the spiral of exercise and dyspnea in COPD patients

Exercise training is the most important component of pulmonary rehabilitation for COPD patients. One of the problems that COPD patients have is that exercise is very difficult. COPD patients are generally short of breath at rest, and exercise augments their hypoxia (oxygen deficiency). This leads to a downward spiral whereby COPD patients to become progressively more sedentary, exacerbating their muscle wasting, leading to more difficulty with exercise and further inactiveness. Pulmonary rehabilitation teaches patients several strategies for exercising for short bouts with COPD. These strategies include a quick inhalation followed by a prolonged pursed lip exhalation. Pursing the lips during exhalation maintains a positive pressure in the lungs keeping the airways open.

Why is exercise so important? First, it helps COPD patients maintain a respiratory reserve at rest. This is critical for surviving an acute exacerbation, such as a pneumonia, which reduces respiratory capacity. Second, it can prevent crippling muscle loss during an exacerbation (Resistance Training Prevents Deterioration in Quadriceps Muscle Function During Acute Exacerbations of Chronic Obstructive Pulmonary Disease, 2010. Troosters, et al.). Studies have shown no difference between endurance training and resistance training in their ability to improve the quality of life of rehabilitation participants for COPD (A Systematic Review of Resistance Training Versus Endurance Training in COPD, 2015. Jepsen UW, et al.). Ideally, a pulmonary rehabilitation program for COPD should run at least eight weeks.


Study: Exercise after Dinner to Lower Diabetic Risk Factors

diabetes resistance exercise



A new study suggests that resistance exercise after a dinner meal is more effective at lowering triacylglycerols in the hours following dinner than resistance exercise before a dinner meal.





If you have been diagnosed as diabetic or pre-diabetic your doctor has probably told you that exercise can help slow the progression of diabetes. Does it matter when you exercise and, if so, when is the best time to exercise? A study published this month in the Journal of Applied Physiology attempted to answer this question by measuring insulin, glucose and triacyglycerols in the blood of thirteen patients diagnosed with diabetes who exercised before and after dinner (Postdinner resistance exercise improves postprandial risk factors more effectively than predinner resistance exercise in patients with type 2 diabetes, 2015. Timothy Heden, et al.).

The study found that resistance exercise following dinner did a better job of lowering risk factors in the blood than both exercise before dinner and no resistance exercise. The risk factors were measured in the blood before, during and after the exercise and meal protocol. Each of the thirteen participants partook in each of the three experimental conditions: dinner without exercise, dinner 20-30 minutes after resistance exercise and resistance exercise 45 minutes after dinner.

Exercise was found to lower postdinner insulin and glucose levels relative to the non-exercise control. However, whether the resistance exercise was performed before or after dinner did not produce a significant effect, although there is a slight  decrease trend in glucose and insulin when exercise was performed after dinner. These results are displayed in the figure below. In contrast to that decrease trend, pre-dinner resistance exercise was found to significantly drop pre-dinner glucose levels relative to both non-exercise and postdinner exercise conditions.  

glucose and insulin levels in a diabetic patient following dinner with resistance exercise

With regard to triacylglycerols, post dinner resistance exercise was found to significantly lower total triacylglycerols in the blood in the hours following dinner. Specifically, VLDL-1 was found to be lowered in the post dinner exercise group relative to both no exercise and pre-dinner exercise. VLDL-1 is a very low density lipoprotein responsible for carrying packaged fats from the liver to the rest of the body. VLDL thats not picked up by the body’s tissues can be converted to unwanted LDL (low density lipoproteins) leading to atherosclerosis. VLDL-1 has also been linked to insulin resistance. The figure below illustrates changes in total blood triacylglycerols (TAG).

triacylglycerol levels in a diabetic patient following dinner with resistance exerciseThis study only addresses a small piece of the answer of when to exercise. What about lunch and breakfast? Is the change in triacylglycerols enough to make a difference in diabetes progression? How would these results change with aerobic exercise? If a person with diabetes is trying to decide whether to perform resistance exercise before or after dinner, this data suggests to do it after dinner. However, if a patient found that he or she was consistently putting off exercise until after dinner and then missing any exercise entirely, it would be advantageous to exercise before dinner. Indeed, well being was assessed through out the study. As soft evidence that exercise is an enjoyable activity, well being before dinner was higher in premeal exercisers. After dinner both exercise groups had significantly higher well being than the non exercise group. 

Thus, we can conclude that whether exercise is performed before or after dinner glucose levels, insulin levels, triacylglycerol levels and general well being all stand to benefit from a dosage of resistance exercise.

Pistachios Hamper Endurance Performance

pistachios in bowl


Two weeks of pistachio ingestion are found to hamper performance on a 75-km cycling time trial, possibly due to elevated levels of a raffinose-associated leukotoxin.








Apparently pistachios are not all they are cracked up to be. A study on pistachios and cycling performance found that the nuts hampered performance on a 75 km cycling time trial. The study was ironically sponsored by American Pistachio Growers; they probably were not too happy with the results. The study was published in the November 2014 issue of PLoS One (Influence of Pistachios on Performance and Exercise-induced Inflammation, Oxidative Stress, Immune Dysfunction, and Metabolite Shifts in Cyclists: A Randomized, Crossover Trial; 2014. David C. Nieman, et al.).

The subjects were 19 trained cyclists. Those who ingested 3 ounces of shelled pistachios a day for two weeks saw a 4.8% decline in performance on a 75-km cycling timetrial. The results of the time trial can be seen in the figure below.

The authors reported higher levels of plasma raffinose, sucrose and myo-inositol in the pistachio ingesting group. Raffinose is a trisaccharide found in onions and many legumes. The soluble carbohydrate is a probiotic for beneficial bacteria in the colon that may reduce inflammatory bowel disease and cancer risk. However, raffinose may increase a leukotoxin, 9,10-DiHOME, that negatively impacts mitochondria. Exercise is known to increase gut permeability and may aid in allowing raffinose, sucrose and myo-inositol to leak across the gut.

The leukotoxin 9,10-DiHOME in the plasma was correlated to increases in plasma raffinose although the mechanism is unknown. 9,10-DiHOME impairs mitochondria function by disrupting the inner membrane of mitochondria and inhibiting cytochrome C release. The raffinose-associated increase in 9,10-DiHOME may be responsible for all, some or none of the decline in cycling performance.

It should be noted that the cyclists ingested a total 3 ounces of pistachios immediately before and during the time trial. The authors caution that the metabolites measured likely resulted from chronic ingestion of pistachios because of the time required to digest and catabolize the metabolites. It might be interesting to measure performance with the exclusion of pistachio consumption on the day of the time trial. The message here is to stay away from pistachios on race day.

Melatonin Does More Than Put You to Sleep

melatonin puts woman to sleep


Melatonin, often sold as an over-the-counter sleep aid, can fight inflammation and oxidative damage in muscle tissue following a strenuous bout of exercise.




We have all experienced the satisfaction of a night of deep sleep after a day of strenuous activity. Thus, it comes as no surprise that exercisers report sleeping better than non-exercisers. American marathon great Meb Keflezighi stresses the importance of sleep with daytime naps on top of 8.5 hours of nighttime sleep. Why do our bodies crave sleep after strenuous activity?

Melatonin

One potential explanation may come from melatonin. Melatonin is our bodies' natural regulator of the circadian rhythm; higher doses at nighttime induce sleepiness and low doses during the day keep us awake. As we age, melatonin production from the pineal gland wanes. Thus, melatonin is often used by the elderly to cure insomnia. In addition to its role in regulating the circadian rhythm, melatonin is a powerful antioxidant.

A study published this month in the Journal of Pineal Research found that melatonin treatment could reduce muscle inflammation and oxidative stress in rats following strenuous exercise (Melatonin decreases muscular oxidative stress and inflammation induced by strenuous exercise and stimulates growth factor synthesis, 2014. Leandro da Silva Borges, et al.).  The Brazilian study exercised the rats to exhaustion for 50 minutes and muscles were looked at immediately following, and two hours after, the conclusion of the exercise protocol.  Half the rats were treated with melatonin intraperitoneally for ten days, while the other half were not administered melatonin.

TNF-α, IL-1β and IL-6 skeletal muscle concentrations expressed as ratios of integrated cytokine release with or without melatonin treatment. The values represent the mean ± SE. *P < 0.05 between the melatonin-treated and control groups and ***P < 0.001 between the melatonin-treated and control groups.

A variety of markers for inflammation and oxidative stress were measured. Plasma levels of IL-1ß (an inflammatory signal) were found to increase immediately following exercise: only 2-fold in the melatonin-treated rats and 3.1-fold in the rats not treated with melatonin.  The exercised rats saw an immediate and maintained increase in plasma L-selectin (a chemical marker for inflammatory cells), but melatonin treatment negated the immediate increase and produced a decrease in L-selectin at 2 hours. In the muscle tissue, melatonin mediated a decrease in TNF-alpha, IL-1ß and IL-6. Thus, the anti-inflammatory effects of melatonin were both systematic and localized. The decrease in inflammatory cytokines in muscle is illustrated in the figure above.

Ratios of integrated VEGF release in skeletal muscle with or without melatonin treatment. The values represent the mean ± SE. *P < 0.05 between the melatonin-treated and control groups.

Melatonin increased VEGF, a potent regulator of angiogenesis. VEGF is also known to play a role in regulating oxidation as it is regulated by oxidative stress through reactive oxygen species. The figure to the right demonstrates the ability of melatonin to increase VEGF concentrations in the skeletal muscle following strenuous exercise.

Superoxide dimutase (SOD) activity in skeletal muscle was also found to increase in the melatonin-treated rats following exercise relative to the exercised rats that did not receive melatonin treatment.  SOD is an antioxidant enzyme that removes the harmful superoxide anion. The figure below illustrates the ability of melatonin to increase the levels of SOD in skeletal muscle.

Ratios of superoxide dimutase (SOD) enzyme activity in skeletal muscle with or without melatonin treatment. The values represent the mean ± SE. ***P < 0.001 between the melatonin-treated and control groups.

Oxidative damage is a major cause of pathogenesis in patients with diabetes mellitus, and can lead to tissue necrosis. Interestingly, melatonin treatment has been shown to reduce oxidative damage in exercising rats with diabetes (Protective effect of melatonin on lipid peroxidation in various tissues of diabetic rats subjected to an acute swimming exercise, 2012. Bicer M, et al.). This Turkish study may highlight the therapeutic effects of melatonin following exercise in patients who are sensitive to oxidative stress (i.e. G6PD deficiency).

The mechanism of how melatonin induces anti-inflammatory effects in skeletal muscle following strenuous exercise is still unknown. However, inflammation and oxidation are directly linked, with oxidative damage in the cell being a signal for an inflammatory response to clear out the damaged tissue. Melatonin is a natural substance made from the amino acid tryptophan and is non-toxic even in high doses. For the athlete, melatonin apparently can do more than put him or her to sleep.

Oral Contraceptives Exert Influence on Exercise Physiology

birth control or oral contraception


Oral contraceptives have been found to hinder aerobic performance, but a new study suggests low-dose monophasic oral contraception may not have an effect on endurance performance.




Athletes put in countless hours in practice to achieve minute, but consequential improvements in performance. Therefore, reports that oral contraception may compromise athletic performance have steered many elite female athletes away from using oral contraception. The studies are not conclusive; some studies demonstrated that oral contraception causes measurable declines in performance, while others found no significant difference.  

Three studies published between 2000 and 2003 indicated an oral contraceptive mediated decline in maximal aerobic capacity. However, a study published this month using low-dose monophasic oral contraceptives as the form of birth control found no differences in aerobic capacity (Maximal fat oxidation, but not aerobic capacity, is affected by oral contraceptive use in healthy women, 2014. Laurie Isaco, et al.). Low-dose monophasic oral contraceptives are popular today (e.g. microgestin) and provide a constant dose of estrogen and progesterone over the menstrual cycle.

The researchers looked at twenty-one recreationally active women who were either taking monophasic oral contraception or who were not taking any oral contraception. They found that women on oral contraceptives showed no measurable difference in aerobic capacity. Furthermore, there was no difference in cardiorespiratory parameters between the women on oral contraceptives and women not on oral contraceptives at maximal aerobic capacity. However, the maximum lipid oxidation rate was higher in women taking oral contraceptives. The women on oral contraceptives had a higher %VO2max (percentage of maximum aerobic capacity) at which the maximum lipid oxidation rate was reached (also referred to as Lipoxmax). The figure below demonstrates the effect of low-dose monophasic oral contraceptives on lipid oxidation during exercise.

Influence of oral contraceptive use (OC+ or OC−) on (A) intensity of exercise at which maximum lipid oxidation rate occurs (Lipoxmax, expressed as %VO2max) and (B) maximal lipid oxidation rate (MLOR) in healthy women. Data is displayed as mean ± SD. **, *** is p<0.01 and p<0.001, respectively. MLOR is milligrams of lipids oxidized per minute per kg of fat-free mass (FFM).

The increased lipid oxidation is difficult to interpret in regards to athletic performance. Endurance athletes generally have higher lipid oxidation rates at sub-maximal paces to conserve carbohydrates. Carbohydrates provide more oxygen efficient energy and their depletion is responsible for “the wall” marathoners hit late in the marathon race. As the figure below demonstrates, women on the low-dose monophasic contraception showed no significant difference in VO2Max. However, there is a decreased VO2Max trend in the women on oral contraceptives relative to the women not on oral contraceptives.

Influence of low dose monophasic oral contraceptives (OC+ and OC-) on VO2Max (maximum ml of oxygen consumed in a minute, a measure of aerobic capacity). Data displayed as mean ± SD. NS is no significant difference between groups.

The authors warn against extrapolating this data to trained athletes. It would also be interesting to use a different assay to measure aerobic capacity. For example, higher lipid oxidation may decrease VO2Max, which reflects a race of 7-10 minutes, but might it have the opposite effect at longer races where carbohydrate depletion is a constraint?

The question remains, does oral contraception hinder endurance performance? The best oral contraceptive option for women appears to be low-dose monophasic oral contraception. The jury is still out on whether the low-dose monophasic oral contraception hinders endurance, but any effect would be relatively minor.


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