Evaluating Sexual Dimorphism of the Muscle Spindles and Intrafusal Muscle Fibers in the Medial Gastrocnemius of Male and Female Rats

Gartych, Magdalena; Jackowiak, Hanna; Bukowska, D; Celichowski, Jan

doi:10.3389/fnana.2021.734555

Cited by 7 publications

(14 citation statements)

References 38 publications

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“…After immunofluorescence labeling, the sections were embedded in Mowiol mounting medium (Carl Roth, Karlsruhe, Germany) and analyzed using a laser scanning confocal microscope (LSM 710; Carl Zeiss AG, Oberkochen, Germany), as described elsewhere 39,40 . We observed no difference in the structure of muscle spindles from male and female mice 48 …”

Section: Methodsmentioning

confidence: 83%

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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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Section: Methodsmentioning

confidence: 83%

“…39,40 We observed no difference in the structure of muscle spindles from male and female mice. 48 3 | RESULTS…”

Section: Immunocytochemistrymentioning

confidence: 99%

The effect of methocarbamol and mexiletine on murine muscle spindle function

Watkins¹,

Schuster²,

Gerwin³

et al. 2022

Muscle and Nerve

View full text Add to dashboard Cite

show abstract

“…: 3757). The muscle spindle data taken from Banks [ 11 ] are derived from a broad range in ages (fetal samples – elder specimens) and while our subject range are relatively homogeneous in age and mass it is generally accepted that absolute muscle spindle number does not change throughout ageing [ 22 , 23 ]. The validity of our subject data and subsequent interpretations are supported by the significantly correlated muscle mass against those from Banks [ 11 ] (electronic supplementary material, figure S1b; R 2 = 0.97, p < 0.001).…”

Section: Methodsmentioning

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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“…While less studied than in the brain and human studies are lacking, sex differences may also present in the spinal cord. Male rats have larger spinal cords by weight and a greater number of motoneurons ( 94 ) as well as differences in skeletal muscle fiber morphometry, spindle density, and innervation ( 95 , 96 ). When taken together, it is not too great of a leap to suggest that a component of the neuromuscular system, such as skeletal muscle mass, could mediate the relationship between sex and brain size.…”

Section: Discussionmentioning

confidence: 99%

Confounds in neuroimaging: A clear case of sex as a confound in brain-based prediction

et al. 2022

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Muscle weakness is common in many neurological, neuromuscular, and musculoskeletal conditions. Muscle size only partially explains muscle strength as adaptions within the nervous system also contribute to strength. Brain-based biomarkers of neuromuscular function could provide diagnostic, prognostic, and predictive value in treating these disorders. Therefore, we sought to characterize and quantify the brain's contribution to strength by developing multimodal MRI pipelines to predict grip strength. However, the prediction of strength was not straightforward, and we present a case of sex being a clear confound in brain decoding analyses. While each MRI modality—structural MRI (i.e., gray matter morphometry), diffusion MRI (i.e., white matter fractional anisotropy), resting state functional MRI (i.e., functional connectivity), and task-evoked functional MRI (i.e., left or right hand motor task activation)—and a multimodal prediction pipeline demonstrated significant predictive power for strength (R2 = 0.108–0.536, p ≤ 0.001), after correcting for sex, the predictive power was substantially reduced (R2 = −0.038–0.075). Next, we flipped the analysis and demonstrated that each MRI modality and a multimodal prediction pipeline could significantly predict sex (accuracy = 68.0%−93.3%, AUC = 0.780–0.982, p < 0.001). However, correcting the brain features for strength reduced the accuracy for predicting sex (accuracy = 57.3%−69.3%, AUC = 0.615–0.780). Here we demonstrate the effects of sex-correlated confounds in brain-based predictive models across multiple brain MRI modalities for both regression and classification models. We discuss implications of confounds in predictive modeling and the development of brain-based MRI biomarkers, as well as possible strategies to overcome these barriers.

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Evaluating Sexual Dimorphism of the Muscle Spindles and Intrafusal Muscle Fibers in the Medial Gastrocnemius of Male and Female Rats

Cited by 7 publications

References 38 publications

The effect of methocarbamol and mexiletine on murine muscle spindle function

The effect of methocarbamol and mexiletine on murine muscle spindle function

Skeletal muscle function underpins muscle spindle abundance

Confounds in neuroimaging: A clear case of sex as a confound in brain-based prediction

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