Bone regulates locomotion by sustaining motoneuronal mitochondrial function
- 1Institut Necker Enfants Malades
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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BibTeX
@misc{guitart2026bone,
title = {{Bone regulates locomotion by sustaining motoneuronal mitochondrial function}},
author = {D. Romeo Guitart and T. Tirani and D. Milunov and A. K. Torres-Juacida and B. Lamotte and C. Arenas-Plascencia and S. Durand and I. Nemazanyy and S. Moriceau and S. Saha and G. Karsenty and F. Oury},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.07.750453},
url = {https://www.biorxiv.org/content/10.64898/2026.10.07.750453v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Bone regulates locomotion by sustaining motoneuronal mitochondrial function
AU - D. Romeo Guitart
AU - T. Tirani
AU - D. Milunov
AU - A. K. Torres-Juacida
AU - B. Lamotte
AU - C. Arenas-Plascencia
AU - S. Durand
AU - I. Nemazanyy
AU - S. Moriceau
AU - S. Saha
AU - G. Karsenty
AU - F. Oury
PY - 2026
DA - 2026/10/07
PB - bioRxiv
DO - 10.64898/2026.10.07.750453
UR - https://www.biorxiv.org/content/10.64898/2026.10.07.750453v1
AB - 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.
ER -