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“Well-trained muscle produces an enzyme that purges the body of harmful substances. In this context the muscle’s function is reminiscent of that of the kidney or the liver.” Jorge Ruas, Department of Physiology and Pharmacology, Molecular and Cellular Physiology, Karolinska Institute, Stockholm, Sweden

Trained Muscle Protects the Brain against Stress-Induced Depression

I walk when I feel down or stressed. A new study from Sweden helps to explain why it works. Interestingly, you don’t have to be in the process of exercising.

Exercise has long been used to relieve or prevent depression, but the mechanisms involved have remained largely unknown. Researchers at the Karolinska Institute in Stockholm appear to be on the way to solving the mystery. Dr. Jorge Ruas and his colleagues have found that regular exercise induces changes in skeletal muscle which prevents an enzyme connected with stress-induced depression from crossing the blood-brain barrier. That’s important because it alleviates the need for drugs that must cross the blood-brain barrier to be effective. It also encourages patients—and the rest of us—to fight off mood swings with exercise.

As is often the case, it’s a little more complicated than I have indicated. For one thing, depression comes in many different forms. The researchers say that all of the mechanisms suggested to contribute to depression (nervous system health, brain plasticity, etc.) appear to be affected by physical activity. They say that’s why exercise “has emerged as an important therapeutic alternative.” So the heterogeneity of the disease doesn’t seem to be a confounding factor. Secondly, endurance training is involved here. The form of muscle involved is activated “by endurance-type activity and promotes mitochondrial biogenesis, fatty acid oxidation, angiogenesis, and resistance to muscle atrophy,” Ruas et al wrote. The effect of other forms of exercise remains unclear. (More below.) Lastly, the main study here involves mice. Reassuringly, there is also a side study involving humans.

With that preface, let’s look at the details.

The Swedish researchers used a genetically modified mouse strain with high levels of PGC-1a1 (pronounced PGC-1alpha1) in their muscles and exposed them, along with normal mice, to a highly stressful environment of noises, flashing lights, and irregular sleep patterns. After five weeks, the normal mice showed evidence of depressed behavior, including lethargy and disinterest in food. The genetically modified mice showed no signs of depression.

The explanation, according to the researchers, is that the mice with higher levels of PGC-1a1 in their muscles also had higher levels of an enzyme called KAT, which converts a substance formed during stress (kynurenine) into kynurenine acid. That’s the critical factor, because kynurenine acid is not able to pass from the blood to the brain.

While its exact function isn’t known, high levels of kynurenine are found in mentally ill patients. The Swedish researchers have showed that when normal mice are given kynurenine they act depressed, while mice with increased levels of levels of PGC-1a1 in their muscle were not affected. In fact, the genetically modified mice, never showed elevated kynurenine in their blood, because the KAT in their blood quickly converted it to kynurenine acid, which couldn’t pierce the blood-brain barrier, resulting in a protective mechanism.

Significantly, the high levels of PGC-1a1 in the modified mice mimicked the effects of aerobic exercise. The mice, however, were not made to exercise.

To test the thesis that aerobic exercise would have the same detox effect in humans, the scientists recruited a group of adult volunteers to participate in three weeks of moderate aerobic exercise. At the end of the exercise program, the volunteers had more PGC-1a1 and KAT enzymes in their muscles.

Ruas and his colleagues concluded: “By inducing exercise-mimetic changes specifically in skeletal muscles we have identified a mechanism that reduces the detrimental effects of stress and enhances the resilience to depression. Our work suggests that there is great therapeutic potential in targeting the PGC-1a1-PPARa/o-KAT- Kynurenine pathway in depressive disorders thus harnessing one of the many beneficial effects of exercise training.”

The full study was published September 25, 2014, in the journal Cell. It was also reported in ScienceDaily.com, WashingtonPost.com and Reuters.com.

The next step for Dr. Ruas and colleagues will be to study people with depression who are prescribed physical exercise as therapy. Hopefully, they will assess the effects of different forms of exercise on depression and levels of kynurenine. 

*  *  *

Jamie Ferrugia, a man with a sharp eye for health science news, was the first of several people to alert me to the new Swedish study. He added this perceptive comment/query: “My takeaway is that man cannot live by aerobics alone...resistance training is essential for the muscles to reach full operating capacity and induce a cascade of positive health benefits like those described.  I'll be curious to get your take.”

Jamie is on to something. If mice could be persuaded to cooperate, my bet is that a combination of aerobic and resistance training would produce the best elixir of depression fighting muscle and enzymes. People studies would be more manageable—and therefore telling. We want the most possible well-trained, depression-fighting muscle working for us. Preethi Srikanthan, MD, MS, and colleagues at the David Geffen School of Medicine at UCLA have found that the more muscle mass we have the less likely we are to die prematurely. Resistance training stimulates muscle fibers left untouched by moderate aerobic exercise. Four or five carefully selected resistance training movements can train and strengthen the entire body from head to toe.

 Resistance training allows you to condition every muscle in the body.
Photo by Pat Berrett

Sprint Intervals would also be a good addition to the muscle-conditioning mix for much the same reason.

Dr. Edward Coyle, Department of Kinesiology and Health Education at the University of Texas at Austin, has written that it seems logical that “aerobic endurance performance is only enhanced by aerobic endurance training, but it has been proven wrong in the realm of athletics as well as muscle biochemistry.” Coyle says that the muscle fibers affected in sprint intervals and steady state exercise are different. “All-out sprint training especially stresses…fast twitch muscle fibers that are remarkably and equally responsive as slow twitch muscle fibers in their ability to increase mitochondrial enzyme activity,” Coyle explained. “In fact, the low-intensity aerobic exercise that is typically prescribed for endurance or health is not very effective at increasing aerobic activity in [fast-twitch] muscle fibers, which comprise approximately one-half of the fibers within the muscles of most people,” he continued. “Thus low-intensity aerobic training is not a very effective or efficient method for maximizing aerobic adaptation in skeletal muscle because it generally does not recruit [fast-twitch] fibers.”

Sprint intervals for the whole body condition more muscle than traditional jogging or biking, which concentrate effort in the lower body. That’s why I use and recommend the Schwinn Airdyne which includes a push-pull arm action. Elliptical trainers with arm action, rowers, and ski ergs also train the upper and lower body.

McMaster University professor of kinesiology Stuart Phillips, a leader in studying the synergy between resistance and aerobic training, calls the perceived divergence and exclusivity between aerobic and resistance training “incorrect.” The responses lie instead along a continuum, says Phillips. You cannot have one without some of the other, according to Phillips.

The bottom line is that total muscle conditioning comes from training the whole body with a combination of endurance and strength training; nothing else will bring the muscles to “full operating capacity.” It’s a good bet that includes the “cascade of positive health benefits” described in the Swedish study.

Carol and I do a wide variety of strength and endurance training.
 Hiking in hilly areas builds strength and endurance without pounding the joints.
The emotional high that comes from being outdoors is an added bonus.

Our recent article “How Much Exercise Is Too Much” lays out how I weave the various forms of exercise into a two-week training cycle: http://www.cbass.com/howmuchexercise.htm

For more details on interval training and the aerobic-strength alliance see our book Take Charge.

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