Changes in motor unit properties in <i>SOD1</i> (G93A) rats

Kryściak, Katarzyna; Grieb, Paweł; Celichowski, Jan

doi:10.1002/mus.24196

Cited by 10 publications

(5 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A previous study of the medial gastrocnemius of SOD1G93A rats, found there to be a loss of FF motor units and increase in proportion of S motors units in late stage disease, which match our twitch timing observations slowing down over time 18 . Furthermore, the study found motor unit rise times of fast motor unit types increased in early symptomatic animals.…”

Section: Measurements Of Rise Times Likely Reflect the Altered Distrisupporting

confidence: 91%

Microendoscopy detects altered muscular contractile dynamics in a mouse model of amyotrophic lateral sclerosis

Chen

Sanchez

Schnitzer

et al. 2020

Sci Rep

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a fatal disease involving motor neuron degeneration. Effective diagnosis of ALS and quantitative monitoring of its progression are crucial to the success of clinical trials. Second harmonic generation (SHG) microendoscopy is an emerging technology for imaging single motor unit contractions. to assess the potential value of microendoscopy for diagnosing and tracking ALS, we monitored motor unit dynamics in a B6.SOD1G93A mouse model of ALS for several weeks. prior to overt symptoms, muscle twitch rise and relaxation time constants both increased, consistent with a loss of fast-fatigable motor units. These effects became more pronounced with disease progression, consistent with the death of fast fatigue-resistant motor units and superior survival of slow motor units. From these measurements we constructed a physiological metric that reflects the changing distributions of measured motor unit time constants and effectively diagnoses mice before symptomatic onset and tracks disease state. these results indicate that SHG microendoscopy provides a means for developing a quantitative, physiologic characterization of ALS progression.ALS is a paralytic, fatal neurodegenerative disease characterized by a progressive loss of motor neurons 1 . The first approved drug to treat ALS, riluzole, which only prolongs survival by a few months 2 , was approved over 20 years ago. Since then, over 50 clinical trials 3 have resulted in only 1 new recently approved drug 4 , edaravone, whose effect on survival has yet to be studied. Development of effective treatments has suffered from a lack of methods for early diagnosis and sensitive monitoring of the disease 5 . Patients enter clinical trials at late disease stages that may be too advanced to gain therapeutic benefit, and subtle improvements might be undetectable. Sensitive diagnostics are needed to reduce diagnostic delay so that earlier-stage patients can be identified and participate in clinical trials.To assess if a therapy is effective, it is also important to have biomarkers of disease progression. Currently, the Revised ALS Functional Rating Score (ALSFRS-R) -a numerical score from 0-48 based on assessments of bulbar, limb, and respiratory function 6 -is the predominant clinical method for measuring disease progression. This score is subjective and a sum of multiple metrics, some of which are highly correlated, making changes in the ALSFRS-R score hard to relate to changes in disease state 7 . As new candidate treatments enter clinical trials, the field needs quantitative diagnostics that reflect the neurophysiologic changes in ALS, provide accurate assessments of disease progression, and inform treatment development and usage.To meet this challenge, we examined whether second harmonic generation (SHG) microendoscopy might detect the physiological changes that occur in ALS. SHG microendoscopy is a minimally invasive approach to imaging the twitch contractions of individual motor units in live patients 8 . Myosin filaments within muscle sar-

show abstract

Section: Measurements Of Rise Times Likely Reflect the Altered Distrisupporting

confidence: 91%

Microendoscopy detects altered muscular contractile dynamics in a mouse model of amyotrophic lateral sclerosis

Chen

Sanchez

Schnitzer

et al. 2020

Sci Rep

View full text Add to dashboard Cite

show abstract

“…In contrast, other slow type MNs undergo a hyperexcitable shift in rheobase similar to fast type MNs [ 42 ]. In SOD1 mutant rats, in the terminal phase of the disease, slow MNs reinnervate fast muscle fibers and gain some properties of fast motor units [ 43 ]. Recently, it has been shown in the SOD1-G85R mouse model that MMP9-immunopositive MNs are present in the spinal ventral horn at 4 months of age while electrophysiological investigation reveals a massive loss of fast type MNs at that stage [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

Age-Related Changes in Pre- and Postsynaptic Partners of the Cholinergic C-Boutons in Wild-Type and SOD1G93A Lumbar Motoneurons

et al. 2015

View full text Add to dashboard Cite

Large cholinergic synaptic terminals known as C-boutons densely innervate the soma and proximal dendrites of motoneurons that are prone to neurodegeneration in amyotrophic lateral sclerosis (ALS). Studies using the Cu/Zn-superoxide dismutase (SOD1) mouse model of ALS have generated conflicting data regarding C-bouton alterations exhibited during ALS pathogenesis. In the present work, a longitudinal study combining immunohistochemistry, biochemical approaches and extra- and intra-cellular electrophysiological recordings revealed that the whole spinal cholinergic system is modified in the SOD1 mouse model of ALS compared to wild type (WT) mice as early as the second postnatal week. In WT motoneurons, both C-bouton terminals and associated M2 postsynaptic receptors presented a complex age-related dynamic that appeared completely disrupted in SOD1 motoneurons. Indeed, parallel to C-bouton morphological alterations, analysis of confocal images revealed a clustering process of M2 receptors during WT motoneuron development and maturation that was absent in SOD1 motoneurons. Our data demonstrated for the first time that the lamina X cholinergic interneurons, the neuronal source of C-boutons, are over-abundant in high lumbar segments in SOD1 mice and are subject to neurodegeneration in the SOD1 animal model. Finally, we showed that early C-bouton system alterations have no physiological impact on the cholinergic neuromodulation of newborn motoneurons. Altogether, these data suggest a complete reconfiguration of the spinal cholinergic system in SOD1 spinal networks that could be part of the compensatory mechanisms established during spinal development.

show abstract

“…Thus, our results may not necessarily reflect the behaviour of motor neurones with higher recruitment thresholds. For instance, selective degeneration (Hadzipasic et al., 2014) and accentuated hypo‐excitability (which seems to precede denervation) (Kryściak et al., 2014; Martínez‐Silva et al., 2018) are more prominent in larger motor neurones in rat models of ALS. ALS is a highly heterogenous neurological disease, and different pathology characteristics might play distinct roles in controlling PICs and its effects on motoneuron intrinsic excitability, such as disease stage and rate of progression, site of onset (e.g.…”

Section: Discussionmentioning

confidence: 99%

Longitudinal changes in intrinsic motoneuron excitability in amyotrophic lateral sclerosis are dependent on disease progression

Trajano,

Orssatto,

McCombe

et al. 2023

The Journal of Physiology

View full text Add to dashboard Cite

Increased amplitude of persistent inward currents (PICs) is observed in pre‐symptomatic genetically modified SOD1 mice models of amyotrophic lateral sclerosis (ALS). However, at the symptomatic stage this reverses and there is a large reduction in PIC amplitude. It remains unclear whether these changes in PICs can be observed in humans, with cross‐sectional studies in humans reporting contradictory findings. In people with ALS, we estimated the PIC contribution to self‐sustained firing of motoneurons, using the paired‐motor unit analysis to calculate the Δfrequency (ΔF), to compare the weaker and stronger muscles during the course of disease. We hypothesised that, with disease progression, ΔFs would relatively increase in the stronger muscles; and decline in the weaker muscles. Forty‐three individuals with ALS were assessed in two occasions on average 17 weeks apart. Tibialis anterior high‐density electromyograms were recorded during dorsiflexion (40% of maximal capacity) ramped contractions, followed by clinical tests. ∆F increased from 3.14 (2.57, 3.71) peaks per second (pps) to 3.55 (2.94, 4.17) pps on the stronger muscles (0.41 (0.041, 0.781) pps, standardised difference (d) = 0.287 (0.023, 0.552), P = 0.030). ∆F reduced from 3.38 (95% CI 2.92, 3.84) pps to 2.88 (2.40, 3.36) pps on the weaker muscles (−0.50 (−0.80, −0.21) pps, d = 0.353 (0.138, 0.567), P = 0.001). The ALSFRS‐R score reduced 3.9 (2.3, 5.5) points. These data indicate that the contribution of PICs to motoneuron self‐sustained firing increases over time in early stages of the disease when there is little weakness before decreasing as the disease progresses and muscle weakness exacerbates, in alignment with the findings from studies using SOD1 mice. imageKey points Research on mouse model of amyotrophic lateral sclerosis (ALS) suggests that the amplitude of persistent inward currents (PICs) is increased in early stages before decreasing as the disease progresses. Cross‐sectional studies in humans have reported contradictory findings with both higher and lower PIC contributions to motoneuron self‐sustained firing. In this longitudinal (∼17 weeks) study we tracked changes in PIC contribution to motoneuron self‐sustained firing, using the ΔF calculation (i.e. onset‐offset hysteresis of motor unit pairs), in tibialis anterior muscles with normal strength and with clinical signs of weakness in people with ALS. ΔFs decreased over time in muscles with clinical signs of weakness. The PIC contribution to motoneuron self‐sustained firing increases before the onset of muscle weakness, and subsequently decreases when muscle weakness progresses.

show abstract

Changes in motor unit properties in SOD1 (G93A) rats

Abstract: Changes in MU properties of SOD1 rats have progressive and multidirectional character and speed depending on the MU type.

Cited by 10 publications

References 48 publications

Microendoscopy detects altered muscular contractile dynamics in a mouse model of amyotrophic lateral sclerosis

Microendoscopy detects altered muscular contractile dynamics in a mouse model of amyotrophic lateral sclerosis

Age-Related Changes in Pre- and Postsynaptic Partners of the Cholinergic C-Boutons in Wild-Type and SOD1G93A Lumbar Motoneurons

Longitudinal changes in intrinsic motoneuron excitability in amyotrophic lateral sclerosis are dependent on disease progression

Contact Info

Product

Resources

About