Comparative anatomy of the mammalian neuromuscular junction

Boehm, Ines; Alhindi, Abrar; Leite, Ana S.; Logie, Chandra; Gibbs, Alyssa; Murray, Olivia; Farrukh, Rizwan; Pirie, R. S.; Proudfoot, Christopher; Clutton, R Eddie; Wishart, Thomas M.; Jones, Ross A.; Gillingwater, Thomas H.

doi:10.1111/joa.13260

Cited by 48 publications

(61 citation statements)

References 36 publications

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“…Taken together with our recently published comparative study of mammalian NMJ morphology, 17 it is clear that considerable heterogeneity of NMJ morphology exists both within and between mammals, including humans. Future studies combining a range of morphological and physiological techniques—such as high-resolution imaging, muscle fibre typing, and electrophysiology—will now be required to ascertain the key determinants of structure–function relationships at the NMJ in both health and disease.…”

Section: Discussionmentioning

confidence: 57%

“…TSCs have vital roles to play at the NMJ during development, maturation and after nerve injury or disease. 27 In the current study, we have extended our understanding of species-specific differences at the mammalian NMJ 10 , 17 to show that significant differences are also present in tSC morphology between humans and mice. Despite having similar numbers of tSCs per NMJ, human tSCs were significantly smaller and characterized by a larger non-synaptic area, less AChR coverage, and the presence of both synaptic and non-synaptic placement of nuclei.…”

Section: Discussionmentioning

confidence: 72%

“…To enable high-resolution comparative morphometric analyses of human and mouse terminal Schwann cells (tSCs), we modified our existing tissue sampling and immunohistochemical staining approaches to examine human NMJs in samples of healthy peroneus brevis (PB) muscle obtained from patients undergoing lower limb amputation surgery. 10 , 11 , 17 Importantly, as previously demonstrated, samples were obtained from otherwise healthy regions of the limb, devoid of any pathological changes resulting from the underlying conditions that necessitated surgical amputation. 10 , 11 …”

Section: Resultsmentioning

confidence: 99%

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Terminal Schwann cells at the human neuromuscular junction

Alhindi

Boehm

Forsythe

et al. 2021

Brain Communications

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Terminal Schwann cells are non-myelinating glial cells localised to the neuromuscular junction. They play an important role in regulating many aspects of neuromuscular junction form and function, in health and during disease. However, almost all previous studies of mammalian terminal Schwann cells have used rodent models. Despite a growing awareness of differences in the cellular and molecular anatomy of rodent and human neuromuscular junctions, it remains unclear as to whether these differences also extend to the terminal Schwann cells. Here, we have adapted immunohistochemical protocols to facilitate visualisation and comparative morphometric analyses of terminal Schwann cells at the human and mouse neuromuscular junction. We labelled terminal Schwann cells in the peroneus brevis muscle in six adult mice and five humans with antibodies against S100 protein. All human neuromuscular junctions were associated with at least one terminal Schwann cell, consistent with findings from other species, with an average of ∼1.7 terminal Schwann cells per neuromuscular junction in both humans and mice. In contrast, human terminal Schwann cells were significantly smaller than those of mice (p ≤ 0.01), in keeping with differences in overall synaptic size. Human terminal Schwann cell cytoplasm extended significantly beyond the synaptic boundaries of the neuromuscular junction, whereas terminal Schwann cells in mice were largely restricted to the synapse. Moreover, there was a significant difference in the location of terminal Schwann cell nuclei (p ≤ 0.01), with human terminal Schwann cells having their nuclear compartment located beyond the perimeter of the synapse more than the mouse. Taken together, these findings demonstrate that terminal Schwann cells at the human neuromuscular junction have notable differences in their morphology and synaptic relationships compared to mice. These fundamental differences need to be considered when translating the findings of both neuromuscular junction biology and pathology from rodents to humans.

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Section: Discussionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 72%

Section: Resultsmentioning

confidence: 99%

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Terminal Schwann cells at the human neuromuscular junction

Alhindi

Boehm

Forsythe

et al. 2021

Brain Communications

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“…The endplate diameter showed changes similar to the endplate area, which are minor values in stretching groups. In Boehm et al 36 work, each animal species has a different value of endplate diameter. Indeed, Estrada-Bonilla et al 37 observed the NMJ morphometric characteristics of the upper limbs of healthy and diabetes mellitusinduced rats.…”

Section: Discussionmentioning

confidence: 99%

The previous stretching to resistance training promotes adaptations on the postsynaptic region in different myofiber types

Jacob

Barbosa

Rodrigues

et al. 2021

Preprint

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This investigation revealed the postsynaptic morphological adaptations in static stretching, resistance training, and their association in adult male Wistar rats. We processed the soleus and plantaris muscle for histochemical (muscle hypertrophy) and postsynaptic region imaging techniques. We observed muscle hypertrophy in both groups submitted to resistance training, even though the cross-section area is larger when there is no previous static stretching. The soleus postsynaptic region revealed an increase in compactness and fragmentation index in combined exercise. The resistance training promotes high adaptations in the postsynaptic area of plantaris; moreover, the previous static stretching decreased this area. In conclusion, the neuromuscular system’s components respond according to the myofiber type even though it is the same physical exercise. Besides, static stretching (isolated or combined) plays a crucial role in neuromuscular adaptations.

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“…'fully innervated', 'partially innervated' or 'denervated'), and criteria for NMJ classification can differ, leading to interlaboratory and inter-rater variabilities, thus limiting further analysis [30][31][32][33][34][35][36][37] . Automatic methods include NMJ-morph, an innovative approach based on Image-J software, which has been used to analyse NMJ morphology in different species 38,39 . This platform has widespread use because of its efficiency in measuring morphological NMJ features.…”

Section: Introductionmentioning

confidence: 99%

NMJ-Analyser: high-throughput morphological screening of neuromuscular junctions identifies subtle changes in mouse neuromuscular disease models

Maza

Jarvis

Lee

et al. 2020

Preprint

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The neuromuscular junction (NMJ) is the peripheral synapse formed between a motor neuron axon terminal and a muscle fibre. NMJs are thought to be the primary site of peripheral pathology in many neuromuscular diseases, but innervation/denervation status is often assessed qualitatively with poor systematic criteria across studies, and separately from 3D morphological structure. Here, we describe the development of ‘NMJ-Analyser’, to comprehensively screen the morphology of NMJs and their corresponding innervation status automatically. NMJ-Analyser generates 29 biologically relevant features to quantitatively define healthy and aberrant neuromuscular synapses and applies machine learning to diagnose NMJ degeneration. We validated this framework in longitudinal analyses of wildtype mice, as well as in four different neuromuscular disease models: three for amyotrophic lateral sclerosis (ALS) and one for peripheral neuropathy. We showed that structural changes at the NMJ initially occur in the nerve terminal of mutant TDP43 and FUS ALS models. Using a machine learning algorithm, healthy and aberrant neuromuscular synapses are identified with 95% accuracy, with 88% sensitivity and 97% specificity. Our results validate NMJ-Analyser as a robust platform for systematic and structural screening of NMJs, and pave the way for transferrable, and cross-comparison and high-throughput studies in neuromuscular diseases.

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Comparative anatomy of the mammalian neuromuscular junction

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 48 publications

References 36 publications

Terminal Schwann cells at the human neuromuscular junction

Terminal Schwann cells at the human neuromuscular junction

The previous stretching to resistance training promotes adaptations on the postsynaptic region in different myofiber types

NMJ-Analyser: high-throughput morphological screening of neuromuscular junctions identifies subtle changes in mouse neuromuscular disease models

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