Enhanced low-threshold motor unit capacity during endurance tasks in patients with spinal muscular atrophy using pyridostigmine

Laura E. Habets; Bart Bartels; Jeroen A.L. Jeneson; Fay Lynn Asselman; Marloes Stam; Camiel A. Wijngaarde; Renske I. Wadman; Ruben P.A. van Eijk; Dick F. Stegeman; W. Ludo van der Pol

doi:10.1016/j.clinph.2023.06.024

Enhanced low-threshold motor unit capacity during endurance tasks in patients with spinal muscular atrophy using pyridostigmine

Laura E. Habets, Bart Bartels^*, Jeroen A.L. Jeneson, Fay Lynn Asselman, Marloes Stam, Camiel A. Wijngaarde, Renske I. Wadman, Ruben P.A. van Eijk, Dick F. Stegeman, W. Ludo van der Pol

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Objective: To investigate the electrophysiological basis of pyridostigmine enhancement of endurance performance documented earlier in patients with spinal muscular atrophy (SMA). Methods: We recorded surface electromyography (sEMG) in four upper extremity muscles of 31 patients with SMA types 2 and 3 performing endurance shuttle tests (EST) and maximal voluntary contraction (MVC) measurements during a randomized, double blind, cross-over, phase II trial. Linear mixed effect models (LMM) were used to assess the effect of pyridostigmine on (i) time courses of median frequencies and of root mean square (RMS) amplitudes of sEMG signals and (ii) maximal RMS amplitudes during MVC measurements. These sEMG changes over time indicate levels of peripheral muscle fatigue and recruitment of new motor units, respectively. Results: In comparison to a placebo, patients with SMA using pyridostigmine had fourfold smaller decreases in frequency and twofold smaller increases in amplitudes of sEMG signals in some muscles, recorded during ESTs (p < 0.05). We found no effect of pyridostigmine on MVC RMS amplitudes. Conclusions: sEMG parameters indicate enhanced low-threshold (LT) motor unit (MU) function in upper-extremity muscles of patients with SMA treated with pyridostigmine. This may underlie their improved endurance. Significance: Our results suggest that enhancing LT MU function may constitute a therapeutic strategy to reduce fatigability in patients with SMA.

Original language	English
Pages (from-to)	100-106
Number of pages	7
Journal	Clinical Neurophysiology
Volume	154
Early online date	20 Jul 2023
DOIs	https://doi.org/10.1016/j.clinph.2023.06.024
Publication status	Published - Oct 2023

Bibliographical note

Funding Information:
BB obtained research grants from Prinses Beatrix Spierfonds and Stichting Spieren voor Spieren, both non-profit foundations. He is a member of the scientific advisory board of Scholar Rock. His employer receives fees for SMA-related consultancy activities. JALJ obtained a research grant from Prinses Beatrix Spierfonds, a non-profit foundation. WLP obtained grants from Prinses Beatrix Spierfonds, Stichting Spieren voor Spieren and Vriendenloterij. He is a member of the scientific advisory board of SMA Europe and has served as an ad hoc member of the scientific advisory boards of Biogen and Avexis and as a member of data monitoring committee for Novartis. All other authors report no conflicts of interest.

Funding Information:
The study is supported by grants from Spieren voor Spieren, Prinses Beatrix Spierfonds, Rotary Bussum and VriendenLoterij. The investigators have full access to the data and have the right to publish this data separate and apart from any sponsor.

Publisher Copyright:
© 2023 International Federation of Clinical Neurophysiology

Funding

BB obtained research grants from Prinses Beatrix Spierfonds and Stichting Spieren voor Spieren, both non-profit foundations. He is a member of the scientific advisory board of Scholar Rock. His employer receives fees for SMA-related consultancy activities. JALJ obtained a research grant from Prinses Beatrix Spierfonds, a non-profit foundation. WLP obtained grants from Prinses Beatrix Spierfonds, Stichting Spieren voor Spieren and Vriendenloterij. He is a member of the scientific advisory board of SMA Europe and has served as an ad hoc member of the scientific advisory boards of Biogen and Avexis and as a member of data monitoring committee for Novartis. All other authors report no conflicts of interest. The study is supported by grants from Spieren voor Spieren, Prinses Beatrix Spierfonds, Rotary Bussum and VriendenLoterij. The investigators have full access to the data and have the right to publish this data separate and apart from any sponsor.

Keywords

Fatigability
Muscle electrical activation
Neuromuscular junction
Pyridostigmine
Spinal muscular atrophy

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10.1016/j.clinph.2023.06.024

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Habets, L. E., Bartels, B., Jeneson, J. A. L., Asselman, F. L., Stam, M., Wijngaarde, C. A., Wadman, R. I., van Eijk, R. P. A., Stegeman, D. F., & Ludo van der Pol, W. (2023). Enhanced low-threshold motor unit capacity during endurance tasks in patients with spinal muscular atrophy using pyridostigmine. Clinical Neurophysiology, 154, 100-106. https://doi.org/10.1016/j.clinph.2023.06.024

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title = "Enhanced low-threshold motor unit capacity during endurance tasks in patients with spinal muscular atrophy using pyridostigmine",

abstract = "Objective: To investigate the electrophysiological basis of pyridostigmine enhancement of endurance performance documented earlier in patients with spinal muscular atrophy (SMA). Methods: We recorded surface electromyography (sEMG) in four upper extremity muscles of 31 patients with SMA types 2 and 3 performing endurance shuttle tests (EST) and maximal voluntary contraction (MVC) measurements during a randomized, double blind, cross-over, phase II trial. Linear mixed effect models (LMM) were used to assess the effect of pyridostigmine on (i) time courses of median frequencies and of root mean square (RMS) amplitudes of sEMG signals and (ii) maximal RMS amplitudes during MVC measurements. These sEMG changes over time indicate levels of peripheral muscle fatigue and recruitment of new motor units, respectively. Results: In comparison to a placebo, patients with SMA using pyridostigmine had fourfold smaller decreases in frequency and twofold smaller increases in amplitudes of sEMG signals in some muscles, recorded during ESTs (p < 0.05). We found no effect of pyridostigmine on MVC RMS amplitudes. Conclusions: sEMG parameters indicate enhanced low-threshold (LT) motor unit (MU) function in upper-extremity muscles of patients with SMA treated with pyridostigmine. This may underlie their improved endurance. Significance: Our results suggest that enhancing LT MU function may constitute a therapeutic strategy to reduce fatigability in patients with SMA.",

keywords = "Fatigability, Muscle electrical activation, Neuromuscular junction, Pyridostigmine, Spinal muscular atrophy",

author = "Habets, {Laura E.} and Bart Bartels and Jeneson, {Jeroen A.L.} and Asselman, {Fay Lynn} and Marloes Stam and Wijngaarde, {Camiel A.} and Wadman, {Renske I.} and {van Eijk}, {Ruben P.A.} and Stegeman, {Dick F.} and {Ludo van der Pol}, W.",

note = "Funding Information: BB obtained research grants from Prinses Beatrix Spierfonds and Stichting Spieren voor Spieren, both non-profit foundations. He is a member of the scientific advisory board of Scholar Rock. His employer receives fees for SMA-related consultancy activities. JALJ obtained a research grant from Prinses Beatrix Spierfonds, a non-profit foundation. WLP obtained grants from Prinses Beatrix Spierfonds, Stichting Spieren voor Spieren and Vriendenloterij. He is a member of the scientific advisory board of SMA Europe and has served as an ad hoc member of the scientific advisory boards of Biogen and Avexis and as a member of data monitoring committee for Novartis. All other authors report no conflicts of interest. Funding Information: The study is supported by grants from Spieren voor Spieren, Prinses Beatrix Spierfonds, Rotary Bussum and VriendenLoterij. The investigators have full access to the data and have the right to publish this data separate and apart from any sponsor. Publisher Copyright: {\textcopyright} 2023 International Federation of Clinical Neurophysiology",

year = "2023",

month = oct,

doi = "10.1016/j.clinph.2023.06.024",

language = "English",

volume = "154",

pages = "100--106",

journal = "Clinical Neurophysiology",

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T1 - Enhanced low-threshold motor unit capacity during endurance tasks in patients with spinal muscular atrophy using pyridostigmine

AU - Habets, Laura E.

AU - Bartels, Bart

AU - Jeneson, Jeroen A.L.

AU - Asselman, Fay Lynn

AU - Stam, Marloes

AU - Wijngaarde, Camiel A.

AU - Wadman, Renske I.

AU - van Eijk, Ruben P.A.

AU - Stegeman, Dick F.

AU - Ludo van der Pol, W.

N1 - Funding Information: BB obtained research grants from Prinses Beatrix Spierfonds and Stichting Spieren voor Spieren, both non-profit foundations. He is a member of the scientific advisory board of Scholar Rock. His employer receives fees for SMA-related consultancy activities. JALJ obtained a research grant from Prinses Beatrix Spierfonds, a non-profit foundation. WLP obtained grants from Prinses Beatrix Spierfonds, Stichting Spieren voor Spieren and Vriendenloterij. He is a member of the scientific advisory board of SMA Europe and has served as an ad hoc member of the scientific advisory boards of Biogen and Avexis and as a member of data monitoring committee for Novartis. All other authors report no conflicts of interest. Funding Information: The study is supported by grants from Spieren voor Spieren, Prinses Beatrix Spierfonds, Rotary Bussum and VriendenLoterij. The investigators have full access to the data and have the right to publish this data separate and apart from any sponsor. Publisher Copyright: © 2023 International Federation of Clinical Neurophysiology

PY - 2023/10

Y1 - 2023/10

N2 - Objective: To investigate the electrophysiological basis of pyridostigmine enhancement of endurance performance documented earlier in patients with spinal muscular atrophy (SMA). Methods: We recorded surface electromyography (sEMG) in four upper extremity muscles of 31 patients with SMA types 2 and 3 performing endurance shuttle tests (EST) and maximal voluntary contraction (MVC) measurements during a randomized, double blind, cross-over, phase II trial. Linear mixed effect models (LMM) were used to assess the effect of pyridostigmine on (i) time courses of median frequencies and of root mean square (RMS) amplitudes of sEMG signals and (ii) maximal RMS amplitudes during MVC measurements. These sEMG changes over time indicate levels of peripheral muscle fatigue and recruitment of new motor units, respectively. Results: In comparison to a placebo, patients with SMA using pyridostigmine had fourfold smaller decreases in frequency and twofold smaller increases in amplitudes of sEMG signals in some muscles, recorded during ESTs (p < 0.05). We found no effect of pyridostigmine on MVC RMS amplitudes. Conclusions: sEMG parameters indicate enhanced low-threshold (LT) motor unit (MU) function in upper-extremity muscles of patients with SMA treated with pyridostigmine. This may underlie their improved endurance. Significance: Our results suggest that enhancing LT MU function may constitute a therapeutic strategy to reduce fatigability in patients with SMA.

AB - Objective: To investigate the electrophysiological basis of pyridostigmine enhancement of endurance performance documented earlier in patients with spinal muscular atrophy (SMA). Methods: We recorded surface electromyography (sEMG) in four upper extremity muscles of 31 patients with SMA types 2 and 3 performing endurance shuttle tests (EST) and maximal voluntary contraction (MVC) measurements during a randomized, double blind, cross-over, phase II trial. Linear mixed effect models (LMM) were used to assess the effect of pyridostigmine on (i) time courses of median frequencies and of root mean square (RMS) amplitudes of sEMG signals and (ii) maximal RMS amplitudes during MVC measurements. These sEMG changes over time indicate levels of peripheral muscle fatigue and recruitment of new motor units, respectively. Results: In comparison to a placebo, patients with SMA using pyridostigmine had fourfold smaller decreases in frequency and twofold smaller increases in amplitudes of sEMG signals in some muscles, recorded during ESTs (p < 0.05). We found no effect of pyridostigmine on MVC RMS amplitudes. Conclusions: sEMG parameters indicate enhanced low-threshold (LT) motor unit (MU) function in upper-extremity muscles of patients with SMA treated with pyridostigmine. This may underlie their improved endurance. Significance: Our results suggest that enhancing LT MU function may constitute a therapeutic strategy to reduce fatigability in patients with SMA.

KW - Fatigability

KW - Muscle electrical activation

KW - Neuromuscular junction

KW - Pyridostigmine

KW - Spinal muscular atrophy

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Enhanced low-threshold motor unit capacity during endurance tasks in patients with spinal muscular atrophy using pyridostigmine

Abstract

Bibliographical note

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Keywords

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