Bones, Not Adrenaline, Drives Fight or Flight Response

In the face of a predator or sudden danger, the heart rate speeds up, breathing becomes more rapid, and glucose is pumped throughout the body to ready the person or animal to fight or flee. These physiological changes commonly attributed as the “fight or flight” response, are believed to be triggered to some extent by the hormone adrenaline.

But a recent study by researchers from the Columbia University submits that bony vertebrates can’t produce this response to danger without the skeleton. By studying mice and humans, they found in that almost instantly after the brain recognizes the threat, it instructs the skeleton to flood the bloodstream with ‘osteocalcin’ , a bone-derived hormone, which is needed to activate the fight or flight response.

The study’s senior investigator Gérard Karsenty, MD, Ph.D., chair of the Department of Genetics and Development at Columbia University Vagelos College of Physicians and Surgeons, “In bony vertebrates, the acute stress response is not possible without osteocalcin. It completely changes how we think about how acute stress responses occur. The view of bones as merely an assembly of calcified tubes is deeply entrenched in our biomedical culture”.

Nearly a decade ago, his lab speculated and demonstrated that the skeleton exercises hidden influences on other organs. That research exposed that the skeleton releases osteocalcin, which travels through the bloodstream to affect the biological functions of the pancreas, the brain, muscles, and other organs.

A series of subsequent studies have demonstrated that osteocalcin helps regulate metabolism by growing the ability of cells to take in glucose, improves memory, and aids animals in running faster with greater endurance.

Bone And Its Seemingly Unrelated Effects On Other Organs When in Danger

Karsenty explains, “If you think of bone as something that evolved to protect the organism from danger—the skull protects the brain from trauma, the skeleton allows vertebrates to escape predators, and even the bones in the ear alert us to approaching danger—the hormonal functions of osteocalcin begin to make sense”.

Karsenty hypothesized that if the bone evolved as an escape mechanism from danger then the skeleton should also be involved in the acute stress response that gets activated in the presence of danger. If osteocalcin helps generate the acute stress response, it must work fast i.e. within the first few minutes after danger is detected.

During the latest study, researchers exposed mice to predator urine and other stressors and then investigated for changes in the bloodstream. Inside 2 to 3 minutes, they noticed a spike in osteocalcin levels.

Likewise in people, the researchers noted surges in osteocalcin when they are subjected to the stress of public speaking or cross-examination. Whenever osteocalcin levels increased in the mice, heart rate, body temperature, and blood glucose levels also rose as the fight or flight response kicked in.

On the contrary, genetically engineered mice were unable to make osteocalcin or its receptor was totally indifferent to the stressor.

Karsenty says, “Without osteocalcin, they didn’t react strongly to the perceived danger. In the wild, they’d have a short day.”

As a final test, the researchers were able to trigger an acute stress response in unstressed mice simply by injecting large amounts of osteocalcin.

Adrenaline Is Not Necessary for Fight or Flight

The findings published in the paper titled “Mediation of the acute stress response by the skeleton,” in the Sept. 12 edition of Cell Metabolism, may also enlighten why animals without adrenal glands and adrenal-insufficient patients who are incapable of producing adrenaline or other adrenal hormones, can experience an acute stress response. Among mice, this capability was missing when the mice were unable to produce large amounts of osteocalcin.

“This shows us that circulating levels of osteocalcin are enough to drive the acute stress response,” states Karsenty.

Physiology As the New Frontier of Biology

Physiology may seem like old-fashioned biology, but with the new genetic techniques developed in the last 15 years, it has emerged as a new frontier in science. The ability to deactivate single genes in specific cells inside an animal, and at precise times, has led to the identification of several new inter-organ relationships. The skeleton is just one prominent case as the heart and muscles are also wielding influence over other organs.

Karsenty surmises,  “I have no doubt that there are many more new inter-organ signals to be discovered, and these interactions may be as important as the ones discovered in the early part of the 20th century.”


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