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!

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Staying Physically Active with COVID-19

coronavirus COVID-19

COVID-19 is affecting the daily lives of people across the globe. Exercise can still be performed while maintaining social distance.

Coronavirus Disease 2019 (COVID-19) has spread across the across the globe and is impacting many peoples lives. Should it be impacting our exercise regimen?

First, it is important to know the basic disease facts of COVID-19. The best way to do that is by going to the CDC website. While the CDC does an excellent job of discusing the symptoms, understanding who needs to be tested and how to prevent spread, there is no information about physical activity with COVID-19. In fact, there is little information in the scientific literature on physical activity with COVID-19. 

A case report out of Taiwan describes a woman with COVID-19 who was able to participate in physical activity once her symptoms began to improve (2019 novel coronavirus disease (COVID-19) in Taiwan: Reports of two cases from Wuhan, China, 2020. Huang, et al.). That is about as deep as the literature goes. Lets talk then about the importance then of reducing disease burden in physically active and young individuals.

For the vast majority of people who are able to participate in moderate to strenous physical activity, COVID-19 poses little to no risk of severe complications. These individuals have the pulmonary reserve to fight an insult of the magnitude that COVID-19 would deliver to the lungs. However, it remains important for these individuals to maintain social distancing. The reason for this is similar to herd immunity. Herd immunity is what makes it important to get vaccines. If enough people have immunizations to say, measles, than it becomes difficult for a measles outbreak to occur. This protects those individuals who have a compromised immune system and are unable to get the measles vaccine (MMR vaccine is a live-attenuated virus). The same concept applies here. Young or physically fit individuals are not at risk of complications from COVID-19, but reducing disease burden in this population is important for reducing disease transmission to people who are less capable of mounting a competent immune response.

Social distancing is one of the best ways to reduce disease transmission. Social distancing is when you limit your exposure to other individuals to reduce the possibility of disease transmission. This includes avoiding large events, limiting close interactions with others and practicing good hand hygeine.

Is it still possible to responsibly perform social distancing while maintaining an active lifestyle? The answer is yes. Most professional sports leagues and colleagiate teams are on a hiatus at the moment. Nonetheless, outdoor sports provide little chance of disease transmission among athletes. The outdoors limit disease transmission because the virus gets diluted in the outdoor air. Inside, the virus can become concentrated by one individual who has the virus. This is one of the reasons that influenza or flu season occurs in the winter while everyone is socializing indoors. If you are still concerned, individual outdoor activities such as walking, hiking, running or cycling can provide a great outlet to escape being cramped up in the house. Even individuals who test positive for COVID-19 and are under quarantine could manage to participate in these activities so long as they do not come near others. Backpacking provides a great way to remain physically active while minimizing social interactions with others. Going to the gym on the other hand may increase your risk of transmission. However, the gym is probably no worse than going to the grocery for example.

In summary, its important to practice social distancing to minimize disease spread to the most vulnerable individuals. However, while avoiding the gym could be sensible, now may be the time to go on that backpacking trip you have been planning.

ADHD is inhibited by sport participation

Children participating in organized sports are less likely to report ADHD symptoms even after controlling for overall physical activity.

ADHD is a disease with symptoms defined by its name, inattention and hyperactivity, with onset in childhood. Although symptoms present in childhood, the disease can often go undiagnosed into adulthood. ADHD can be particularly debilitating, leading to decreased classroom productivity and worse job performance. It's thought that TV and other electronics have contributed to the rise of ADHD. One recently published study out of Australia found that children ages 9-11 who participated in organized sports were less likely to have ADHAD symptoms. (Associations between organised sport participation and classroom behavior outcomes among primary school-aged children, 2019. Watson A, et al.). This association held up even after adjusting for overall physical activity.

The authors suggest that parents may have another reason to consider organized sports as a means of physical activity for their children. 

Prostate Cancer Decreases with Fitness


Prostate cancer occurs at lower rates and has reduced mortality in those who are physically active. 

Prostate cancer is the most common cancer to afflict American men, with one in six men being diagnosed with prostate cancer at some point during their lifetime. Adding it all up, over 200,000 Americans are diagnosed with prostate cancer every year. Fortunately, the prognosis of prostate cancer is relatively good, especially if diagnosed early. Nonetheless, prostate cancer remains the second most common cause of cancer death in males (second to lung cancer, the number one cause of cancer fatalities in both men and women, but ahead of colorectal cancer). 

Risk factors for prostate cancer include increased age and black race. Asian men are at reduced risk. In addition to their higher incidence of prostate cancer, black men tend to develop more aggressive forms of prostate cancer. These risk factors are not modifiable, are there any modifiable risk factors?

Diet and exercise have both been found to be associated with risk of developing prostate cancer. Diets high in fat have been shown to increase risk of prostate cancer. One epidemiological study found Hawaiians were far more likely to develop prostate cancer if they had high dietary intake of beef or high-animal fat products (Animal fat consumption and prostate cancer: a prospective study in Hawaii, 1994. Le Marchand, et al.). Subsequent studies have supported this association between high-fat diet and prostate cancer. 

Two studies have found prostate cancer to be reduced with physical activity. Although smoking has been linked with many cancer, it has not been linked with prostate cancer. One study found that there was a reduction in the incidence of prostate cancer in individuals who reported participating in vigorous physical activity. (Does physical activity reduce the risk of prostate cancer? A systemic review and meta-analysis, 2011. Liu, et al.). This link was particularly strong for individuals who reported physical activity at work. Another study demonstrated a reduced risk of fatal prostate cancer in individuals who reported physical activity (Risk factors for prostate cancer incidence and progression in the health professionals follow-up study, 2007. Giovannucci, et al.).

Although smoking has been linked with many types of cancer, it has not been linked with prostate cancer. 

Does Marijuana Affect Athletic Performance?


Chronic marijuana use is shown by one study to have no effect on aerobic or anaerobic performance. 

Marijuana use has been increasing in popularity over the last several years, especially with the legalization of recreational marijuana in large states such as Colorado and California. A study was recently conducted in Colorado to evaluate the effects of chronic marijuana use on anaerobic and aerobic fitness (Performance and Health Related Characteristics of Physically Active Males using Marijuana, 2018. Lisano JK, et al.).

Marijuana use is especially prevalent in young adults, the age when athletes are in their prime. In fact, 20% of young adults report using marijuana in the last month. In 1999, marijuana was added to the banned substances list by the World Anti-Doping Agency. More recently, marijuana was banned by the NCAA for college athletes in the US. Nonetheless, a one study found that 37% of NCAA Division I athletes reported using marijuana, with the prevalence higher in male athletes compared to female athletes. However, does marijuana really help improve athletic performance?

Marijuana is known to have a number of effects on the body. Marijuana use has been shown to be linked with higher rates of depression and anxiety, but also has successfully treated asthma, migraines, glaucoma and seizures. Marijuana has been used to treat nausea associated with chemotherapy, but its withdrawal can cause whats known as cyclic vomiting syndrome. Medical evidence supports the use of THC, the active ingredient in marijuana, in treating nausea and emesis, muscle spasms in adults with multiple sclerosis and chronic pain. Marijuana is also thought to have prenatal effects when used by pregnant women, although studies out of Jamaica where it used to control morning sickness dispute this. In terms of physiology, marijuana use causes an increase in the resting heart rate and acute use increases airway conductance. Marijuana is known to decrease oxidative capacity of mitochondria in skeletal muscle (and theoretically therefore aerobic performance). Chronic marijuana use decreases testosterone in males and raises cortisol (produced in response to stress).

In regards to performance, the aforementioned study conducted by researchers in Colorado evaluated 24 males, half chronic marijuana users (at least weekly use) and half having abstained from marijuana for the last year. The study found no difference between the groups pulmonary function (assessed with FEV1), cardiovascular function (assessed with VO2 max), muscle endurance (assessed with planks and grip strength) or anaerobic performance (assessed with peak power output). However, there was a trend towards decreased power output in the marijuana users, which may be significant in a larger cohort. The study did find that chronic marijuana users had higher blood levels of CRP (C-reactive protein), a marker of inflammation.

So what does this mean? Despite some athletes having the impression that marijuana can increase athletic performance, this is unlikely. If anything, these results suggest that marijuana may decrease power output, and would therefore not be recommended for athletes in sports were power output is important such as weightlifting. Caution should be utilized in interpreting the results of this relatively small study, further research will be necessary to get a more definitive picture of marijuana’s affect on athletic performance.

Exercise Can Alleviate the Side Effects of Chemotherapy

woman on chemotherapy running on the beach

Chemotherapy produces some nasty side effects, but new research suggests that exercise can alleviate one of the most painful side effects, peripheral neuropathy, in cancer patients.

Unfortunately, cancer treatment produces some very unpleasant side effects for the patients that receive them. The side effects can be so severe that patients are forced to pause or withdraw from potentially lifesaving therapy. One of the most painful side effects of chemotherapy is neuropathy, which produces sharp tingling sensations, numbness and hot or cold feelings. The pain usually manifests in the fingers or toes before progressing up the extremities. The pain, like diabetic neuropathy, likely originates from damage or inflammation to the peripheral nerves although the mechanism is not completely understood. Unfortunately, relieving chemotherapy-induced peripheral neuropathy relies on symptomatic treatment, often requiring opiates that carry their own set of short-term and long-term consequences. 

A clinical trial examining the ability of exercise to alleviate peripheral neuropathy symptoms in cancer patients receiving chemotherapy has yielded promising results (Effects of exercise during chemotherapy on chemotherapy-induced peripheral neuropathy: a multicenter, randomized controlled trial, 2018. Ian Kleckner, et al.). The trial was a large, randomized control trial accruing patients at 20 community cancer centers who were receiving neurotoxic chemotherapy such as taxanes, platinum-based chemotherapy or vinca alkaloid-based chemotherapy. The exercise intervention consisted of 6 weeks of unsupervised walking exercise and 6 weeks of unsupervised exercise with resistance bands. Following exercise just 36.5% of patients reported neuropathic symptoms compared to 49.2% of patients that did not exercise. The patients who exercised reported significantly reduced severity of neuropathic pain as well as less hot and cold symptoms. There was a trend toward reduced numbness and tingling in the exercise group (see figure below). 

Exercise reduces the severity of chemotherapy-induced peripheral neuropathy symptoms per patient-reported numbness and tingling (left; trend-level effect) and hot/coldness in hands/feet (right). Error bars show 95% confidence intervals from 170 exercise patients and 185 control patients. The p-values correspond to differences in exercise and control conditions from linear regression.

The results of this study suggest that walking and resistance exercise can be used to alleviate neuropathic symptoms in cancer patients receiving neurotoxic chemotherapy. The exercise regimens were relatively easy to perform and this allowed the patients to perform the exercises at home. Further studies will need to be conducted to determine the optimal exercise regimens for cancer patients with neuropathic pain. 

Exercise Reduces the Addiction to Smoking

running while smoking

Research finds that a short, intense bout of exercise reduces the urge to smoke, cravings to smoke and withdrawal symptoms.

Can exercise help you quit smoking? According to one recent study the answer is yes. The study (Effect of brief exercise on urges to smoke in men and women smokers, 2018. Alicia Allen, et al.) was published in the journal of Addictive Behaviors. The researchers recruited 38 men and women who were heavy smokers, smoking at least 5 cigarettes per day, for the study. The participants cycled at their maximum VO2 capacity for 6-12 minutes. A questionnaire was completed before and 15 minutes after the cycling exercise to assess smoking addiction. There was a reduction in smoking addiction symptoms after the brief cycling exercise in all categories assessed on the questionnaire: withdrawal, cravings, total smoking urges, intention to smoke and anticipated relief from negative affect. There were no gender differences among groups. 

A mechanism for how smoking reduces smoking addiction has not been elucidated. However, it easy to postulate such a mechanism. Exercise produces a dopamine surge in the brain, producing what is popularly referred to as “runner’s high”. The biology of addiction similarly relies on dopamine surges. Dopamine surges in the brain in response to cigarettes, or other addictive substances such as alcohol or drugs. The addiction strengthens as the brain generates less of a dopamine surge in response to addictive substance. In other words, addiction is simply a yearning for that dopamine surge in the brain produced by the addictive substance. Exercise’s ability to produce that dopamine surge in the brain probably explains the results in the aforementioned study.

Although exercise can reduce addiction symptoms 15 minutes after the exercise session, this may not necessarily translate to hours after the exercise. As exercising every 15 minutes would be impractical, further trials need to be conducted to determine if the effects on smoking addiction have long-term implications. 

Sitting Raises Your Blood Sugar

Standing desk

A recent study finds that individuals who sat for a prolonged period of time had trouble controlling their blood sugar, interestingly intermittent standing brought blood sugar under control.

Advocates for standing desks continue to be backed by further evidence demonstrating the harmful effects of prolonged sitting. The latest research on the subject found that not only was standing beneficial, but it actually was superior to a moderate exercise bout in controlling blood sugar levels after a meal.

The study was published last November in the journal Medicine & Science in Sports & Exercise. The study (Intermittent Standing but not a Moderate Exercise Bout Reduces Postprandial Glycemia, 2017. Benatti FB, et al.) randomized 14 physically inactive healthy adult males to four different physical activity groups: prolonged sitting for 9 hours, 9 hours of alternating between sitting and standing every 15 minutes, prolonged sitting for 8.5 hours with a 30-minute moderate-intensity treadmill run, and a combination group consisting of a 30-minute moderate-intensity treadmill run and sitting with 15 minute standing breaks every half hour for 8 hours. Participants were excluded if they had a known diagnosis of diabetes. The researchers found that glucose levels following breakfast (postprandial) on the day of the intervention were lower in all groups with standing and/or moderate physical activity compared to the group with 9 hours of continuos sitting. Interestingly, when the researchers looked at glucose control after breakfast on the day after the sitting or exercise intervention they found that the group that had intermittent standing, but not the group that had a moderate bout of physical activity, had superior glucose control. This finding may suggest that intermittent standing may have a longer protective effect rather than a single bout of moderate physical activity on glycemic control. 

The mechanism by which standing mediates improvements in glycemic control are thought to originate from the contracting muscle in the legs during standing taking up glucose and fatty acids. This increases the sensitivity of body tissues to insulin, which is the hormone that mediates uptake of glucose from the blood. This study did not find any effect of standing on fat and lipid control in the blood following eating. Further work may be necessary to determine the effect of standing on other health indicators such as hypertension.

Indeed, many individuals follow a schedule of a single daily episode of physical activity followed by prolonged sitting at home and/or work for the remainder of the day. In terms of glucose control, which is a marker of diabetes mellitus, it appears that a trip to the gym in the morning is not enough to cancel out a day of sitting. Intermittent standing appears to be a solution. 

How can one incorporate intermittent standing into their daily lives? In many ways, its easier than a trip to the gym in the morning. A standing desk is probably the most obvious solution, but there are other simple lifestyle changes one can make. For example, while watching TV consider using commercial breaks as an excuse to stand up from the couch. Or, while at the office, set a timer on your phone or watch to remind you to stand up every half hour. Such reminders come standard on many smartwatches now.

With that being said, its time to stand up!

Aerobic Exercise for 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.


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 with 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 an 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 component 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.

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