Exercise in a pill…again?

When life gets rough, I go out for a run. A sweet tune, a steady pace, a great view and all the anxiety and stress that plague me melt away. Though tough to get into, exercise is not only beneficial for your cardiovascular health, but also improves cognition and mood. For those who’ve suffered strokes, exercise may be even more effective than drugs in prolonging life.

Scientists have chased down the brain health benefits of exercise to a protein called brain-derived neurotrophic factor (BDNF). This protein nourishes existing neurons and promotes their survival; it also encourages the growth of new neurons and the formation of synapses, which neurons use to communicate with each other. In the hippocampus, a brain region vital for learning, memory and mood, BDNF supports the formation of long-term memories and is a crucial component of the molecular machinery that mediate anti-depressant effects.

Researchers have long searched for ways to increase BDNF without resorting to cardio, that is, to recreate the benefits of exercise in a pill. While this would not necessarily help the general public, it may allow those unable to engage in physical activity to enjoy the health of endurance without exertion. Unfortunately, BDNF itself is too large to cross the blood-brain barrier; it needs to be directly injected into the brain to work. Worth it? Probably not!

An alternative strategy is to focus on messengers that link the body to the brain. In other words, how does exercise, which happens in the body, increase BDNF in the brain?

Christiane Wrann et al (2013). Exercise Induces Hippocampal BDNF through a PGC-1α/FNDC5 Pathway. Cell metabolism. doi: 10.1016/j.cmet.2013.09.008

Enter our two candidate proteins, both of which are expressed in skeletal muscle and increase with exercise. PGC-1alpha prepares your muscles for longer and harder abuse by increasing the number of cellular energy factories (mitochondria), allowing better energetics. This protein is a transcription coactivator; that is, it promotes the expression of other downstream proteins, one of them being FNDC5, aka irisin. In the periphery, irisin “transforms” beige fat into the more metabolically active brown fat to support thermogenesis and maintain a healthy metabolism; in the brain, it seems to help neurons mature – but not much else is known. Could these two exercise-induced proteins be the messengers?

The researchers gave a bunch of male mice a running wheel, and watched them for 30 days. Lab mice are as enthusiastic about running as your average pet hamster; give them a wheel and they’ll go at it for hours. After their final bouts of exercise, researchers looked into their brains and found an increase in both proteins, specifically in the hippocampus (graph B below; green- running; black-sedentary) but not in the remainder of the brain (graph C). This boost of irisin paralleled a small increase in BDNF, again only in the hippocampus.

Fndc5 is irisin; Erra is also an exercise-related protein which works with PGF-1alpha to increase gene expression.

Fndc5 is irisin; Erra is also an exercise-related protein which works with PGF-1alpha to increase gene expression.

Is irisin CAUSING more BDNF expression? Researchers used a virus to deliver a strongly expressed version of the irisin gene into isolated cortical (not hippocampal!) neurons in culture; this forces neurons to produce more irisin than they would naturally. As you can see below, this treatment (blue) caused an increase in BDNF, as well as MANY other proteins induced in neuronal activation (viral-delivered Green Fluorescent Protein/GFP, black bars, was used as a control).

On the other hand, when researchers used three different short “hairpin”-like strand of synthetic RNA (shRNA) to inhibit irisin RNA expression, BDNF levels tanked (crimson bars) compared to the control (black bar).

Since BDNF is linked to neuronal survival, researchers next checked to see how they faired. As predicted, forced expression of irisin increased the number of surviving neurons, while eliminating the protein had the opposite affect (though this could be due to toxicity of the shRNA). Further investigation found that BDNF inhibited irisin expression in a negative feedback loop, presumably to keep protein levels steady.

Neurons in culture can’t give us the whole picture. Researchers next turned to mice. When they forced the liver (why not skeletal muscle?) to overexpress irisin, once again BDNF increased in the hippocampus but not other areas of the brain. The effect size however, as you can see below, is TINY. Again, many other proteins were upregulated.

So here we have a problem: irisin increases BDNF in the hippocampus in mice; nevertheless, researchers used cortical neurons for most of their studies. What happens if they switched to cultured hippocampal neurons instead?

The curse of negative data. As you can see below in graph D, stimulation of hippocampal neurons with synthetic irisin (blue bars) did NOT significantly raise BDNF levels (no star on the BDNF blue bar), though it did induce expression of many other proteins. When researchers eliminated irisin with three different shRNAs (graph E, Fndc5=irin, black bar is control; see how shRNAs cause a drop in its levels?), two of them also caused a decrease in BDNF as expected (shFndc5-1 and shFndc 5-2). The third? Not so much.

So what’s the verdict? While exercise no doubt increases BDNF in the hippocampus, irisin alone most likely doesn't. The data clearly shows that the effect size is either VERY small, as in their animal model, or non-existent! Furthermore, irisin is quite promiscuous: it increases the expression of other genes as well. These genes, known together as “immediate-early genes”, are expressed right after neuronal activation, and can also lead to an increase in BDNF levels. Hence it’s impossible to conclude that exercise increases irisin in the periphery, which in turn boosts BNDF in the hippocampus and bam! Less anxiety and better memory.

Irisin may mediate the benefits of exercise in skeletal tissue (this is also debated); but I wouldn’t bet on it as a potential exercise pill for brain health. Apparently, some people do – the lead author is chair of Ember therapeutics, a company that among other things focuses on irisin for the treatment of metabolic syndrome.

Scientists have so far uncovered several target proteins that recapitulate the effects of exercise when increased individually. Whether a single drug can mimic the mind-boggling spectrum of physiological and psychological effects of exercise though is another question. While scientists continue on their search, me? I’m going for a run.

Christiane D. Wrann, James P. White, John Salogiannnis, Dina Laznik-Bogoslavsk, Jun Wu, Di Ma, Jiandie D. Lin, Michael E. Greenberg, & Bruce M. Spiegelman (2013). Exercise Induces Hippocampal BDNF through a PGC-1a/FNDC5 Pathway Cell Metabolism : met.2013.09.008