The effect of methocarbamol and mexiletine on murine muscle spindle function

Abstract

Introduction/Aims: The muscle relaxant methocarbamol and the antimyotonic drug mexiletine are widely used for the treatment of muscle spasms, myotonia, and pain syndromes. To determine whether these drugs affect muscle spindle function, we studied their effect on the resting discharge and on stretch-induced action potential frequencies of proprioceptive afferent neurons.Methods: Single unit action potential frequencies of proprioceptive afferents from muscle spindles in the murine extensor digitorum longus muscle of adult C57BL/6J mice were recorded under resting conditions and during ramp-and-hold stretches.Maximal tetanic force of the same muscle after direct stimulation was determined.High-resolution confocal microscopy analysis was performed to determine the distribution of Na v 1.4 channels, a potential target for both drugs.Results: Methocarbamol and mexiletine inhibited the muscle spindle resting discharge in a dose-dependent manner with IC 50 values around 300 μM and 6 μM, respectively. With increasing concentrations of both drugs, the response to stretch was also affected, with the static sensitivity first followed by the dynamic sensitivity.At high concentrations, both drugs completely blocked muscle spindle afferent output. Both drugs also reversibly reduced the specific force of the extensor digitorum longus muscle after tetanic stimulation. Finally, we present evidence for the presence and specific localization of the voltage-gated sodium channel Na v 1.4 in intrafusal fibers.Discussion: In this study we demonstrate that both muscle relaxants affect muscle spindle function, suggesting impaired proprioception as a potential side effect of both drugs. Moreover, our results provide additional evidence of a peripheral activity of methocarbamol and mexiletine.

Degeneration of muscle spindles in a murine model of Pompe disease

“…6 A,B) revealed few contractile filaments in the central region of intrafusal fibers in 8-month-old wildtype animals, in agreement with the almost complete absence of sarcomeres in this region (Fig. 6 A 25 ). In contrast, S46 staining was readily observed throughout the central region of intrafusal fibers in category 3-like muscle spindles from age-matched Gaa −/− mice (Figs.…”

“…Similar to the myosin heavy chain, we observed a concentration of Na v 1.4 immunoreactivity specifically in the subsarcolemmal compartment of the central region of intrafusal fibers in wildtype muscle spindles (Fig. 6 C 25 ), but a presence of this channel throughout the intrafusal fiber, including the equatorial region, in 8-month-old Gaa −/− mice (Fig. 6 D).…”

“…To confirm the redistribution of proteins in the central region of intrafusal fibers, we compared the distribution of the voltage-gated sodium channel Na v 1.4 in 8-month-old wildtype and Gaa −/− mice. The immunoreactivity for this channel is coextensive with the phalloidin-labeled actin filaments in intrafusal muscle fibers from wildtype mice 25 , and therefore an indicator of the contractile apparatus. Similar to the myosin heavy chain, we observed a concentration of Na v 1.4 immunoreactivity specifically in the subsarcolemmal compartment of the central region of intrafusal fibers in wildtype muscle spindles (Fig.…”

“…In contrast, it appeared throughout the intrafusal fiber in degenerating muscle spindles from 8-month old Gaa −/− mice. Similarly, the nuclear bag fiber-specific myosin heavy chain 6 (stained by the S46 antibody) labeled only the subsarcolemmal sarcomeres in the central region of wildtype intrafusal fibers 25 but was present throughout the central part of intrafusal fibers in 8-month-old Gaa −/− mice. This suggests that intrafusal fibers change the subcellular distribution of their cytoskeleton and of associated molecules in degenerating muscle spindles.…”

“…Among others, we observed that several proteins usually almost exclusively present in both polar regions of intrafusal fibers redistributed into the central (equatorial) region of intrafusal fibers in 8-month-old Gaa −/− mice. For example, the voltage-gated sodium channel Na v 1.4 was present in the central region of wildtype muscle spindles only as a thin layer underneath the plasma membrane 25 . In contrast, it appeared throughout the intrafusal fiber in degenerating muscle spindles from 8-month old Gaa −/− mice.…”