Ketolysis is required for the proper development and function of the somatosensory nervous system.

Autor: Enders J; Departments of Anesthesiology, University of Kansas Medical Center, Kansas City, KS 66160, United States of America., Jack J; Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS 66160, United States of America., Thomas S; Departments of Anesthesiology, University of Kansas Medical Center, Kansas City, KS 66160, United States of America., Lynch P; Departments of Anesthesiology, University of Kansas Medical Center, Kansas City, KS 66160, United States of America., Lasnier S; Departments of Anesthesiology, University of Kansas Medical Center, Kansas City, KS 66160, United States of America., Cao X; Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS 66160, United States of America., Swanson MT; Departments of Anesthesiology, University of Kansas Medical Center, Kansas City, KS 66160, United States of America., Ryals JM; Departments of Anesthesiology, University of Kansas Medical Center, Kansas City, KS 66160, United States of America., Thyfault JP; Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS 66160, United States of America; Internal Medicine - Division of Endocrinology, University of Kansas Medical Center, Kansas City, KS 66160, United States of America; KU Diabetes Institute, University of Kansas Medical Center, Kansas City, KS 66160, United States of America., Puchalska P; Department of Medicine, Division of Molecular Medicine, University of Minnesota, Minneapolis, MN, 55455, United States of America., Crawford PA; Department of Medicine, Division of Molecular Medicine, University of Minnesota, Minneapolis, MN, 55455, United States of America; Department of Molecular Biology, Biochemistry, and Biophysics, University of Minnesota, Minneapolis, MN 55455, United States of America., Wright DE; Departments of Anesthesiology, University of Kansas Medical Center, Kansas City, KS 66160, United States of America; KU Diabetes Institute, University of Kansas Medical Center, Kansas City, KS 66160, United States of America. Electronic address: dwright@kumc.edu.
Jazyk: angličtina
Zdroj: Experimental neurology [Exp Neurol] 2023 Jul; Vol. 365, pp. 114428. Date of Electronic Publication: 2023 Apr 24.
DOI: 10.1016/j.expneurol.2023.114428
Abstrakt: Ketogenic diets are emerging as protective interventions in preclinical and clinical models of somatosensory nervous system disorders. Additionally, dysregulation of succinyl-CoA 3-oxoacid CoA-transferase 1 (SCOT, encoded by Oxct1), the fate-committing enzyme in mitochondrial ketolysis, has recently been described in Friedreich's ataxia and amyotrophic lateral sclerosis. However, the contribution of ketone metabolism in the normal development and function of the somatosensory nervous system remains poorly characterized. We generated sensory neuron-specific, Advillin-Cre knockout of SCOT (Adv-KO-SCOT) mice and characterized the structure and function of their somatosensory system. We used histological techniques to assess sensory neuronal populations, myelination, and skin and spinal dorsal horn innervation. We also examined cutaneous and proprioceptive sensory behaviors with the von Frey test, radiant heat assay, rotarod, and grid-walk tests. Adv-KO-SCOT mice exhibited myelination deficits, altered morphology of putative Aδ soma from the dorsal root ganglion, reduced cutaneous innervation, and abnormal innervation of the spinal dorsal horn compared to wildtype mice. Synapsin 1-Cre-driven knockout of Oxct1 confirmed deficits in epidermal innervation following a loss of ketone oxidation. Loss of peripheral axonal ketolysis was further associated with proprioceptive deficits, yet Adv-KO-SCOT mice did not exhibit drastically altered cutaneous mechanical and thermal thresholds. Knockout of Oxct1 in peripheral sensory neurons resulted in histological abnormalities and severe proprioceptive deficits in mice. We conclude that ketone metabolism is essential for the development of the somatosensory nervous system. These findings also suggest that decreased ketone oxidation in the somatosensory nervous system may explain the neurological symptoms of Friedreich's ataxia.
Competing Interests: Declaration of Competing Interest P.A.C. has consulted for Pfizer, Inc., Abbott Laboratories, and Jansen Research & Development. The other authors declare no competing financial interests.
(Copyright © 2023. Published by Elsevier Inc.)
Databáze: MEDLINE
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