Abstract
Sensitive and objective biomarkers of neuronal injury, degeneration, and regeneration can help facilitate translation of experimental findings into clinical testing. Whereas measures of upper motor neuron connectivity have been readily established, functional assessments of lower motor neuron (LMN) innervation of forelimb muscles are lacking. Compound muscle action potential (CMAP) and motor unit (MU) number estimation (MUNE) are well-established methods that allow longitudinal MU integrity monitoring in patients. In analogy we refined CMAP and MUNE methods for assessing spinal MU input in the rat forelimb and hindlimb. Repeated CMAP and MUNE recordings are robust (coefficients of variability: 4.5–11.3%), and MUNE measurements from forelimb wrist flexor muscles (415 ± 8 [SEM]) align with back-traced anatomical LMN counts (336 ± 16 [SEM]). For disease validation, cross-sectional blinded electrophysiological and muscle contractility measurements were obtained in a cohort of G93A SOD1 mutant overexpressing rats and compared with controls. Longitudinal assessment of mutant animals demonstrated progressive motor unit decline in the hindlimb to a greater extent than the forelimb. Hindlimb CMAP and MUNE demonstrated strong correlations with plantarflexion muscle contractility. Cross-species assessment of upper/fore- limb and lower/hind- limb motor units using objective electrophysiological CMAP and MUNE values as biomarkers will guide and improve bi-directional translation.
Highlights
Can result in preserved Compound muscle action potential (CMAP) amplitude and area despite motor unit (MU) loss
The incremental MU number estimation (MUNE) technique was first reported in the early 1970s in the extensor digitorum brevis muscle in humans as a means to track the number of motor neurons functionally connected to a particular muscle[7]
In the forelimb, we recorded from the ventromedial forearm (Fig. 2A), which overlies the wrist flexor muscles
Summary
Can result in preserved CMAP amplitude and area despite MU loss. To address this limitation, the CMAP technique has been modified to assess MU number and size. The incremental MU number estimation (MUNE) technique was first reported in the early 1970s in the extensor digitorum brevis muscle in humans as a means to track the number of motor neurons functionally connected to a particular muscle[7]. MUNE can sensitively identify and track motor unit loss and is able to identify MU dysfunction prior to other measures such as CMAP amplitude or area[8,9]. This is most strikingly demonstrated in ALS patients, where MUNE has emerged as one of the most sensitive biomarkers of disease onset, progression, and prognosis[10,11]. We sought to validate CMAP and MUNE as sensitive objective biomarkers of longitudinal motor unit degeneration and dysfunction by obtaining repeated recordings from SOD1 transgenic rats, which model ALS
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