Bone regulates locomotion by sustaining motoneuronal mitochondrial function

Romeo Guitart, D.; Tirani, T.; Milunov, D.; Torres-Juacida, A. K.; Lamotte, B.; Arenas-Plascencia, C.; Durand, S.; Nemazanyy, I.; Moriceau, S.; Saha, S.; Karsenty, G.; Oury, F.

doi:10.64898/2026.10.07.750453

bioRxiv · 10.64898/2026.10.07.750453

Bone regulates locomotion by sustaining motoneuronal mitochondrial function

Romeo Guitart, D.·Tirani, T.·Milunov, D.·Torres-Juacida, A. K.·Lamotte, B.·Arenas-Plascencia, C.·Durand, S.·Nemazanyy, I.·Moriceau, S.·Saha, S.·Karsenty, G.·Oury, F.

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Abstract

Body-brain communication is crucial for optimal neuronal performance across the lifespan, yet whether peripheral organs regulate spinal cord motoneuron (MN) function through circulating molecules remains unknown. The expression of hormone receptors by spinal MNs raises the possibility that circulating cues allow the spinal cord to sense the body's energetic state and sustain motor activity. Here, we show that the bone-derived hormones osteocalcin (OCN) signals on spinal MNs via its receptor GPR158. GPR158 is selectively enriched in spinal cholinergic MNs, and its loss, globally or specifically in spinal MNs, or the one of OCN, impairs locomotor function and reduces choline acetyltransferase (ChAT) levels. Mechanistically, OCN signaling through GPR158 fine-tunes autophagy, mitophagy and mitochondrial activity in spinal MNs. Restoring any of these processes, by pharmacologically inducing mitophagy or chemogenetically activating mitochondria, is sufficient to rescue the locomotor deficits of Gpr158-deficient mice. Finally, OCN restoration in aged mice reverses age-related locomotor decline through a mechanism that requires MN autophagy and mitophagy. This study reveals that through OCN, the skeleton influences motor functions by fine-tuning motoneuronal mitochondria, and suggests that age-related motor decline is, at least in part, reversible.

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Romeo Guitart, D., Tirani, T., Milunov, D., Torres-Juacida, A. K., Lamotte, B., Arenas-Plascencia, C., Durand, S., Nemazanyy, I., Moriceau, S., Saha, S., Karsenty, G., Oury, F.. 2026-10-08. Bone regulates locomotion by sustaining motoneuronal mitochondrial function. https://doi.org/10.64898/2026.10.07.750453

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