The bone-derived hormone osteocalcin (OCN) acts on spinal motoneurons via the receptor GPR158 to regulate autophagy, mitophagy, and mitochondrial activity. Mice lacking GPR158 globally or specifically in spinal motoneurons, or lacking OCN itself, show impaired locomotion and reduced choline acetyltransferase (ChAT) levels. Crucially, restoring mitophagy pharmacologically or activating mitochondria chemogenetically rescued locomotor deficits in GPR158-deficient animals. In aged mice, OCN supplementation reversed age-related motor decline through a mechanism dependent on motoneuron autophagy and mitophagy.
This preprint — not yet peer-reviewed — extends an increasingly compelling body of work from the Karsenty lab positioning the skeleton as an endocrine organ that communicates with the nervous system. Earlier research established osteocalcin's roles in muscle performance, memory, and stress responses; this study adds spinal motor function to that list, with a mechanistic link to mitochondrial quality control. For adults, the finding is provocative: age-related muscle weakness and gait decline may be partly driven by falling osteocalcin levels — a modifiable signal rather than irreversible neuronal loss. Physical exercise is already the best-established way to boost circulating osteocalcin in humans, reinforcing exercise's neurological benefits beyond cardiovascular fitness. Key limitations include the exclusively mouse-based evidence, making human translation uncertain. Whether exogenous osteocalcin supplementation is safe or feasible in people remains untested. Still, the reversal of locomotor decline in aged animals is a striking result that warrants rigorous follow-up in human cohorts.