Posted on by Dr. Francis Collins
There’s no doubt that exercise is good for us—strengthening our muscles, helping us maintain a healthy weight, maybe even boosting our moods and memories. There’s also been intriguing evidence that exercise may help build strong bones.
Now, an NIH-funded study is shedding light on the mechanism behind exercise’s bone-strengthening benefits . The new work—which may lead to new approaches for treating osteoporosis, a disease that increases the risk of bone fracture—centers on a hormone called irisin that is secreted by muscles during exercise.
In a series of mouse experiments, the researchers found that irisin works directly on a common type of bone cell, stimulating the cells to produce a protein that encourages bones to thin. However, this chain of molecular events ultimately takes a turn for the better and reverses bone loss.
Bruce Spiegelman’s lab at the Dana-Farber Cancer Institute and Harvard University Medical School, Boston, first discovered the irisin hormone in 2012 . In the years since, evidence has accumulated suggesting a connection between irisin and many of the benefits that come with regular workouts. For example, delivering low doses of irisin—sometimes called “the exercise hormone”—increase bone density and strength in mice.
But how does irisin act on bones? The answer hasn’t been at all clear. A major reason is the protein receptor on our cells that binds and responds to irisin wasn’t known.
In the new study reported in the journal Cell, Spiegelman’s team has now identified irisin’s protein receptor, called αVβ5 integrin. Those receptors are present on the surface of osteocytes, the most common cell type found in mature bone tissue.
The researchers went on to show that irisin helps osteocytes to live longer. It also leads the bone cells to begin secreting a protein called sclerostin, known for its role in preparing bones for remodeling and rebuilding by first breaking them down. Interestingly, previous studies also showed sclerostin levels increase in response to the mechanical stresses that come with exercise.
To further explore the role of irisin in mouse studies, the researchers gave the animals the hormone for six days. And indeed, after the treatment, the animals showed higher levels of sclerostin in their blood.
The findings suggest that irisin could form the basis of a new treatment for osteoporosis, a condition responsible for almost nine million fractures around the world each year. While it might seem strange that a treatment intended to strengthen bone would first encourage them to break down, this may be similar to the steps you have to follow when fixing up a house that has weakened timbers. And Spiegelman notes that there’s precedent for such a phenomenon in bone remodeling—treatment for osteoporosis, parathyroid hormone, also works by thinning bones before they are rebuilt.
That said, it’s not yet clear how best to target irisin for strengthening bone. In fact, locking in on the target could be a little complicated. The Speigelman lab found, for example, that mice prone to osteoporosis following the removal of their ovaries were paradoxically protected from weakening bones by the inability to produce irisin.
This new study fits right in with other promising NIH-funded efforts to explore the benefits of exercise. One that I’m particularly excited about is the Molecular Transducers of Physical Activity Consortium (MoTrPAC), which aims to develop a comprehensive map of the molecular changes that arise with physical activity, leading to a range of benefits for body and mind.
Indeed, the therapeutic potential for irisin doesn’t end with bone. In healthy people, irisin circulates throughout the body. In addition to being produced in muscle, its protein precursor is produced in the heart and brain.
The hormone also has been shown to transform energy-storing white fat into calorie-burning brown fat. In the new study, Spiegelman’s team confirms that this effect on fat also depends on the very same integrin receptors present in bone. So, these new findings will no doubt accelerate additional study in Speigelman’s lab and others to explore the many other benefits of irisin—and of exercise—including its potential to improve our moods, memory, and metabolism.
 Irisin Mediates Effects on Bone and Fat via αV Integrin Receptors. Kim H, Wrann CD, Jedrychowski M, Vidoni S, Kitase Y, Nagano K, Zhou C, Chou J, Parkman VA, Novick SJ, Strutzenberg TS, Pascal BD, Le PT, Brooks DJ, Roche AM, Gerber KK, Mattheis L, Chen W, Tu H, Bouxsein ML, Griffin PR, Baron R, Rosen CJ, Bonewald LF, Spiegelman BM. Cell. 2018 Dec 13;175(7):1756-1768.
 A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Boström P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, Rasbach KA, Boström EA, Choi JH, Long JZ, Kajimura S, Zingaretti MC, Vind BF, Tu H, Cinti S, Højlund K, Gygi SP, Spiegelman BM. Nature. 2012 Jan 11;481(7382):463-8.
Guide to Physical Activity (National Heart, Lung, and Blood Institute/NIH)
Spiegelman Lab (Dana-Farber Cancer Institute, Boston)
Molecular Transducers of Physical Activity in Humans (Common Fund/NIH)
Video: MoTrPAC (Common Fund)
NIH Support: National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute; National Institute on Aging; National Institute of Neurological Disorders and Stroke
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