The bone hormone osteocalcin supports motor neuron mitochondria through GPR158, and restoring it reverses age-related mobility loss in mice
The bone hormone osteocalcin supports motor neuron mitochondria through GPR158, and restoring it reverses age-related mobility loss in mice
The laboratories of Gerard Karsenty and Franck Oury have shown that bone directly regulates spinal motor neuron function through the hormone osteocalcin. The signal acts through the receptor protein GPR158 on the surface of these neurons, regulating mitochondrial clearance and function. In old mice, this signaling weakens as mobility declines, and restoring the hormone restores both.
Bone was long regarded as a supporting structure, but in 2007, Karsenty and colleagues at Columbia University first showed that the skeleton is an endocrine organ: it secretes osteocalcin, a hormone that regulates metabolism. The same group later found that osteocalcin acts on the brain, affecting memory and anxiety, and on muscles. These are two of the three components that work together to control movement. The third, the spinal cord, remained untested.
A new preprint posted on bioRxiv on October 8 addresses this gap. Without starting from a specific hypothesis, the authors examined which hormone receptors were active in different mouse spinal cord cells and mapped their interaction networks for each cell type. Motor neurons, the cells that transmit signals from the spinal cord to muscles, showed the greatest dependence on these receptors, with GPR158 among the most important in this cell type. Motor neurons have the longest axons in the body and the highest energy demands, making mitochondrial quality control particularly important for them. GPR158 is also the receptor through which osteocalcin acts on the brain.
To establish that the effect originated in motor neurons themselves, the authors deleted GPR158 throughout the spinal cord or specifically in motor neurons, or deleted osteocalcin itself. In all three cases, mice performed worse on a rotating rod and a balance beam while moving normally in an open field. The impairment was specific to coordination, with overall activity preserved.
An unbiased analysis of spinal cord proteins identified the process controlled by this signal: osteocalcin acts through GPR158 to regulate autophagy, the process by which cells break down and recycle their own worn components. This includes the clearance of damaged mitochondria, called mitophagy. Pharmacological activation of autophagy or mitophagy fully restored coordination in mice lacking GPR158. Direct chemical stimulation of mitochondrial function also worked, even without restoring this clearance pathway. Thus, either clearing damaged mitochondria or boosting the function of working mitochondria was sufficient on its own.
In 16-month-old mice, whose balance has already deteriorated, the same pathway declines naturally: both spinal cord GPR158 levels and markers of autophagy fall. A month of osteocalcin treatment restored performance on coordination tests in old mice and restored levels of choline acetyltransferase, an enzyme required for neurons to transmit signals to muscles. When autophagy or mitophagy was first disabled specifically in the spinal cord, the hormone no longer produced this recovery. This shows that osteocalcin restores mobility through the same mechanism that declined with age.
The findings come from mice in which the receptor or hormone gene was deleted, and the effect in aging was tested by administering the hormone directly. The paper has yet to undergo peer review, and the contribution of GPR37, the other known osteocalcin receptor, was not examined separately. In late August, an analysis of sarcopenia, the age-related loss of muscle strength and mobility, examined the individual components involved in movement. It showed that mobility can differ even at the same muscle volume, depending on which component along the path from brain to muscle has weakened. Here, age-related mobility loss results from the weakening of one such component, the hormonal signal between bone and the spinal cord. Restoring that signal can, in principle, reverse the decline.