Efficacy of exogenous pyruvate in Trembler(J) mouse model of Charcot-Marie-Tooth neuropathy.
Brain Behav. 2018 Oct;8(10):e01118. doi: 10.1002/brb3.1118. Epub 2018 Sep 21.
Efficacy of exogenous pyruvate in TremblerJ mouse model of Charcot-Marie-Tooth neuropathy.
Sahenk Z1,2,3,4, Yalvac ME1, Amornvit J1,5,6, Arnold WD4,7, Chen L1, Shontz KM1, Lewis S1.
Classic Charcot-Marie-Tooth (CMT) neuropathies including those with Schwann cell genetic defects exhibit a length-dependent process affecting the distal axon. Energy deprivation in the distal axon has been the proposed mechanism accounting for length-dependent distal axonal degeneration. We hypothesized that pyruvate, an intermediate glycolytic product, could restore nerve function, supplying lost energy to the distal axon.
To test this possibility, we supplied pyruvate to the drinking water of the Trembler-J (TrJ ) mouse and assessed efficacy based on histology, electrophysiology, and functional outcomes. Pyruvate outcomes were compared with untreated TrJ controls alone or adeno-associated virus mediated NT-3 gene therapy (AAV1.NT-3)/pyruvate combinatorial approach.
Pyruvate supplementation resulted increased myelinated fiber (MF) densities and myelin thickness in sciatic nerves. Combining pyruvate with proven efficacy from AAV1.tMCK.NT-3 gene therapy provided additional benefits showing improved compound muscle action potential amplitudes and nerve conduction velocities compared to pyruvate alone cohort. The end point motor performance of both the pyruvate and the combinatorial therapy cohorts was better than untreated TrJ controls. In a unilateral sciatic nerve crush paradigm, pyruvate supplementation improved myelin-based outcomes in both regenerating and the contralateral uncrushed nerves.
This proof of principle study demonstrates that exogenous pyruvate alone or as adjunct therapy in TrJ may have clinical implications and is a candidate therapy for CMT neuropathies without known treatment.
© 2018 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.
CMT neuropathies; NT-3; exogenous pyruvate; improved nerve function
PMID: 30239155 PMCID: PMC6192403 DOI: 10.1002/brb3.1118