Molecular correlates of muscle spindle and Golgi tendon organ afferents

Oliver, Katherine M.; Florez-Paz, Danny M.; Badea, Tudor C.; Mentis, George Z.; Menon, Vilas; Nooij, Joriene C. de

doi:10.1038/s41467-021-21880-3

Cited by 46 publications

(65 citation statements)

References 75 publications

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“…With further developments and improved resolution of medical imaging techniques, it may one day be possible to differentiate the more viscus-filled spindle capsules from the surrounding extrafusal fibres [ 4 ]. However, the recent identification of molecular signatures for each individual afferent subtype (muscle spindle; groups Ia, II and Golgi tendon organs; Ib) [ 45 ] may pave the way to better understanding of the organization and function of the proprioceptive system during locomotion in animal models. Finally, our data may provide guidance to better tailor physiotherapy strategies for trauma/pathologically impaired proprioception, where there there is no gold standard exercise rehabilitation protocol to promote recovery; rather a combination of exercise tasks is used to challenge the CNS for rehabilitation [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

Skeletal muscle function underpins muscle spindle abundance

et al. 2022

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Muscle spindle abundance is highly variable within and across species, but we currently lack any clear picture of the mechanistic causes or consequences of this variation. Previous use of spindle abundance as a correlate for muscle function implies a mechanical underpinning to this variation, but these ideas have not been tested. Herein, we use integrated medical imaging and subject-specific musculoskeletal models to investigate the relationship between spindle abundance, muscle architecture and in vivo muscle behaviour in the human locomotor system. These analyses indicate that muscle spindle number is tightly correlated with muscle fascicle length, absolute fascicle length change, velocity of fibre lengthening and active muscle forces during walking. Novel correlations between functional indices and spindle abundance are also recovered, where muscles with a high abundance predominantly function as springs, compared to those with a lower abundance mostly functioning as brakes during walking. These data demonstrate that muscle fibre length, lengthening velocity and fibre force are key physiological signals to the central nervous system and its modulation of locomotion, and that muscle spindle abundance may be tightly correlated to how a muscle generates work. These insights may be combined with neuromechanics and robotic studies of motor control to help further tease apart the functional drivers of muscle spindle composition.

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Section: Discussionmentioning

confidence: 99%

Skeletal muscle function underpins muscle spindle abundance

et al. 2022

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“…23,33 Several sodium channels have been localized in muscle spindles by immunocytochemistry. 49 50 It remains to be solved, however, which of these sodium channels is the target of mexiletine and/or methocarbamol in muscle spindles. Both drugs are promiscuous with respect to the sodium channels they interact with, but the strong similarity of the effect of both drugs on the muscle spindle resting discharge and the stretch-induced action potentials suggest that both drugs affect muscle spindles via the same sodium channel.…”

Section: Discussionmentioning

confidence: 99%

The effect of methocarbamol and mexiletine on murine muscle spindle function

Watkins¹,

Schuster²,

Gerwin³

et al. 2022

Muscle and Nerve

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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.

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“…Instead, neuroanatomically mapping the spinal and brainstem targets of sensory ganglion neurons has relied on tracers and well-defined molecular markers of neuronal types. This is the case even for recently identified sensory neuron subtypes ( Häring et al, 2018 ; Oliver et al, 2021 ; H. Wu et al, 2021 ). The use of AAV-PHP.S, particularly in combination with Cre-dependent expression, enhances the experimenter’s toolbox, allowing precise and efficient labeling of peripheral neurons while leaving resident neurons in the central target field unlabeled.…”

Section: Discussionmentioning

confidence: 88%

Selectively Imaging Cranial Sensory Ganglion Neurons Using AAV-PHP.S

Asencor

Dvoryanchikov

Makhoul

et al. 2022

eNeuro

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Because of their ease of use, adeno-associated viruses (AAVs) are indispensable tools for much of neuroscience. Yet AAVs have been used relatively little to study the identities and connectivity of peripheral sensory neurons, principally because methods to selectively target peripheral neurons have been limited. The introduction of the AAV-PHP.S capsid with enhanced tropism for peripheral neurons ( Chan et al., 2017 ) offered a solution, which we further elaborate here. Using AAV-PHP.S with GFP or mScarlet fluorescent proteins, we show that the mouse sensory ganglia for cranial nerves V, VII, IX, and X are targeted. Pseudounipolar neurons of both somatic and visceral origin, but not satellite glia, express the reporters. One week after virus injection, ≈66% of geniculate ganglion neurons were transduced. Fluorescent reporters were transported along the central and peripheral axons of these sensory neurons, permitting visualization of terminals at high resolution, and in intact, cleared brain using light sheet microscopy. Further, using a Cre-dependent reporter, we demonstrate by anatomic and functional criteria, that expression is in a cell type-selective manner. Finally, we integrate earlier neuroanatomical and molecular data with in vivo Ca 2+ imaging to demonstrate the sensory characteristics of geniculate ganglion auricular neurons, which were previously undocumented. Our analyses suggest that the AAV-PHP.S serotype will be a powerful tool for anatomically and functionally mapping the receptive fields and circuits of the expanding numbers of molecular subtypes of many somatosensory and viscerosensory neurons that continue to be defined via single-cell RNA sequencing.

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Molecular correlates of muscle spindle and Golgi tendon organ afferents

Cited by 46 publications

References 75 publications

Skeletal muscle function underpins muscle spindle abundance

Skeletal muscle function underpins muscle spindle abundance

The effect of methocarbamol and mexiletine on murine muscle spindle function

Selectively Imaging Cranial Sensory Ganglion Neurons Using AAV-PHP.S

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