Osteocalcin: The New Rejuvenator

4. October 2016

Whoever thinks of bone only in terms of it as the supporting skeleton for the body is being misguided. Using an injection of the hormone osteocalcin derived from skeletal tissue, researchers succeeded "rejuvenating" mice. Another study showed that osteocalcin ensures the preservation of muscle mass in old age.

Specialists at the WADA (World Anti-Doping Agency) and other doping laboratories have certainly already caught sight of this substance, even if it has not yet appeared on the market: osteocalcin. A hormone in the skeleton tissue through which power and performance can be increased? According to a publication in the journal Cell Metabolism this protein born in bone brings tired and old muscle back to where it once was in its youth.

Energy demanding bone remodelling

Bone as a human organ singularly possesses a specialised cell type which is only responsible for tissue breakdown. Osteoclasts together with the corresponding constituent actors, osteoblasts, deal with the constant cell conversions during growth in the first stage of human life, as well as those involved after injuries. In addition however a good deal of energy is required, which must be supplied when requested. Researchers some time later, yet not really surprisingly, discovered a protein that ensures that sugar and fatty acids become the fuel for the active cells in the bone. During its maturity process osteocalcin ends up with more carboxyl groups appended and thus has a strong affinity for mineral ions, especially calcium. A small portion of manufactured osteocalcin however migrates in uncarboxylated form into the circulatory system and there takes up functions as a hormone.

Already several years ago, researchers – in particular the team led by Gerard Karsenty from New York’s Columbia University – demonstrated that osteocalcin lowers blood sugar levels and inhibits fat storage. In his experiments using mice which overexpressed osteocalcin and exhibited large amounts of uncarboxylated protein in the blood, the scientists observed the deaths of many baby mice during lactation. They had extremely low blood sugar and high insulin levels.

Age-related: muscle power and osteocalcin

In their current experiments Karsenty and his colleagues however came across a previously unknown link between the adjacent tissues of bone and muscle. “Never before could anyone show”, says Karsenty “that the bone affects the muscles in any way”. Whereas insulin acts by promoting the uptake of glucose in the muscle cells, the pancreatic hormone cannot govern degradation and thus ATP production. During sporting exercise a drop in insulin levels also occurs. Osteocalcin on the other hand increases sharply during physical work, especially in young mice. In contrast, both muscle mass as well as performance drop in older mice exactly as in humans.

This in turn is reflected in the osteocalcin content in the blood, which in elderly mice only moderately increases with effort. In three months old mice, peak levels at the 40-minute point of an endurance run in a wheel are about four times as high as in mice aged twelve months. Younger mice manage about 1.2 kilometres as one singular effort, whereas about half that distance leaves the older mice fully listless. Mice with a defect in the osteocalcin receptor managed about a quarter less distance than those with the natural genome. With increasing age, the levels of this bone hormone continuously sink in macaque monkeys and humans. In women this process begins at the age of 30, in men not until 15 to 20 years later.

The most striking thing however for the mice researchers from New York was the possibility of “rejuvenating” old animals with osteocalcin. With a single injection of uncarboxylated osteocalcin, one-year old rodents also managed to run the 1200m track without getting tired.

Collaboration with Il-6

In order to elucidate the molecular processes behind the effect of osteocalcin on energy production in the muscle, the scientists measured the levels of glucose, glycogen and acylcarnitines as markers of fatty acid catabolism. Yet osteocalcin can do apparently even more. It regulates its own synthesis through IL-6. This myokine in turn stimulates the bone to produce more osteocalcin (see graphic). What’s more IL-6 in the liver ensures glucose replenishment, and IL-6 together with adipocytes provide fatty acids which are made available for combustion. With intense exercise, Il-6 levels in the blood also rise.


Effect of osteocalcin in the muscle cell © Mera et al /CellMetabolism 2016

In a second short publication in Molecular Metabolism the team led by Karsenty describes yet another collaboration between bony osteocalcin and muscle. Tested once again on mice, the hormone is responsible for the preservation of muscle mass with increasing age. It promotes protein building in the tubules without influencing its breakdown. What’s more, osteocalcin injections achieve a significant increase in muscle mass in nine month old rodents.

Information for sex and memory

Previous studies already made us aware of other capabilities of this hormonal “all rounder”. In Leydig cells it helps in testosterone synthesis. Patients with a osteocalcin-receptor mutation also often have in addition to the symptoms of testosterone deficiency impaired glucose tolerance. Eventually, the bone hormone also overcomes the blood-brain barrier and binds to serotonergic neurons and thus also manages neurotransmitter release. Meanwhile, there is even speculation about whether age-related memory loss might not somehow be related to declining osteocalcin levels.

The current knowledge about osteocalcin was derived by the research group at Columbia University and other teams most abundantly from work on mouse. Should the system be found to work very similarly in humans, osteocalcin could have a spectacular career ahead. Not only as a potential doping agent, but as a pharmaceutical agent to stop muscle breakdown in old age: a remedy against increasing frailty to have in the hand – and in the bone.


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