Motor Unit Remodeling Research Articles

Differential training benefits and motor unit remodeling in wrist force precision tasks following high and low load blood flow restriction exercises under volume-matched conditions

BackgroundBlood flow restriction (BFR) resistance training has demonstrated efficacy in promoting strength gains beneficial for rehabilitation. Yet, the distinct functional advantages of BFR strength training using high-load and low-load protocols remain unclear. This study explored the behavioral and neurophysiological mechanisms that explain the differing effects after volume-matched high-load and low-load BFR training.MethodsTwenty-eight healthy participants were randomly assigned to the high-load blood flow restriction (BFR-HL, n = 14) and low-load blood flow restriction (BFR-LL, n = 14) groups. They underwent 3 weeks of BFR training for isometric wrist extension at intensities of 25% or 75% of maximal voluntary contraction (MVC) with matched training volume. Pre- and post-tests included MVC and trapezoidal force-tracking tests (0–75%–0% MVC) with multi-channel surface electromyography (EMG) from the extensor digitorum.ResultsThe BFR-HL group exhibited a greater strength gain than that of the BFR-LL group after training (BFR_HL: 26.96 ± 16.33% vs. BFR_LL: 11.16 ± 15.34%)(p = 0.020). However, only the BFR-LL group showed improvement in force steadiness for tracking performance in the post-test (p = 0.004), indicated by a smaller normalized change in force fluctuations compared to the BFR-HL group (p = 0.048). After training, the BFR-HL group activated motor units (MUs) with higher recruitment thresholds (p < 0.001) and longer inter-spike intervals (p = 0.002), contrary to the BFR-LL group, who activated MUs with lower recruitment thresholds (p < 0.001) and shorter inter-spike intervals (p < 0.001) during force-tracking. The discharge variability (p < 0.003) and common drive index (p < 0.002) of MUs were consistently reduced with training for the two groups.ConclusionsBFR-HL training led to greater strength gains, while BFR-LL training better improved force precision control due to activation of MUs with lower recruitment thresholds and higher discharge rates.

No ageing-related increase in fibre type grouping in sprint-trained masters runners: A 10-year follow-up study.

Previous research suggests that an ageing-associated remodelling and loss of motor units due to motor neuron death contributes significantly to muscle weakness in old age. In histological sections, motor unit remodelling is reflected by increased fibre type grouping. While regular exercise may not attenuate the loss of motor units during ageing, it has been suggested to facilitate reinnervation resulting in larger motor units, and a higher number and larger fibre type groups in histological sections of muscles from aged individuals. In a 10-year follow-up study, we assessed changes in the prevalence and size of fibre type groups in the vastus lateralis muscle from 34 male masters sprinters (40-85years at start). Over the 10years, there was an ageing-related reduction in performance in the 60-m sprint (P<0.001) without significant changes in fibre type composition and fibre cross-sectional area. Neither the number of fibre type groups, defined as a fibre surrounded exclusively by fibres of the same type, nor the group size changed significantly in the 10-year period. These histological data show that there is limited to no significant fibre type grouping over a 10-year period in masters athletes who continued sprint run training. This observation challenges the paradigm that ageing, at least in systematically trained sprinters, is associated with motor unit remodelling.

The impact of life-long strength versus endurance training on muscle fiber morphology and phenotype composition in older men.

Aging is typically associated with decreased muscle strength and rate of force development (RFD), partly explained by motor unit remodeling due to denervation, and subsequent loss of fast-twitch type II myofibers. Exercise is commonly advocated to counteract this detrimental loss. However, it is unclear how life-long strength versus endurance training may differentially affect markers of denervation and reinnervation of skeletal myofibers and, in turn, affect the proportion and morphology of fast-twitch type II musculature. Thus, we compared fiber type distribution, fiber type grouping, and the prevalence of atrophic myofibers (≤1,494 µm2) in strength-trained (OS) versus endurance-trained (OE) master athletes and compared the results to recreationally active older adults (all >70 yr, OC) and young habitually active references (<30 yr, YC). Immunofluorescent stainings were performed on biopsy samples from vastus lateralis, along with leg press maximal strength and RFD measurements. OS demonstrated similar type II fiber distribution (OS: 52.0 ± 16.4%; YC: 51.1 ± 14.4%), fiber type grouping, maximal strength (OS: 170.0 ± 18.9 kg, YC: 151.0 ± 24.4 kg), and RFD (OS: 3,993 ± 894 N·s-1, YC: 3,470 ± 1,394 N·s-1) as young, and absence of atrophic myofibers (OS: 0.2 ± 0.7%; YC: 0.1 ± 0.4%). In contrast, OE and OC exhibited more atrophic fibers (OE: 1.2 ± 1.0%; OC: 1.1 ± 1.4%), more grouped fibers, and smaller proportion of type II fibers (OE: 39.3 ± 11.9%; OC: 35.0 ± 12.4%) than OS and YC (all P < 0.05). In conclusion, strength-trained master athletes were characterized by similar muscle morphology as young, which was not the case for recreationally active or endurance-trained old. These results indicate that strength training may preserve type II fibers with advancing age in older men, likely as a result of chronic use of high contractile force generation.NEW & NOTEWORTHY Aging is associated with loss of fast-twitch type II myofibers, motor unit remodeling, and grouping of myofibers. This study reveals, for the first time, that strength training preserves neural innervation of type II fibers, resulting in similar myofiber type distribution and grouping in life-long strength-trained master athletes as young moderately active adults. In contrast, life-long endurance-trained master athletes and recreationally active old adults demonstrated higher proportion of type I fibers accompanied by more marked grouping of type I myofibers, and more atrophic fibers compared with strength-trained master athletes and young individuals. Thus, strength training should be utilized as a training modality for preservation of fast-twitch musculature, maximal muscle strength, and rapid force capacity (RFD) with advancing age.

Sensitivity Analysis of CMAP Scan Step Index to Different Stimulation Parameters and Examination of Muscles Affected by Spinal Cord Injury.

Step index (STEPIX) is a recently developed compound muscle action potential (CMAP) scan method for evaluating motor unit loss and remodeling changes. This study investigates the influence of different stimulation parameters during CMAP scan on STEPIX and its examination of muscles affected by spinal cord injury (SCI). CMAP scan of the first dorsal interosseous (FDI) muscle was performed using different stimulus pulse widths (0.1 ms, 0.2 ms) and different numbers of stimuli (500, 1000) in 12 neurologically intact subjects. STEPIX was derived from each CMAP scan of all subjects. A significantly higher STEPIX was obtained using 1000 stimuli than 500 stimuli, while no significant difference in STEPIX was observed using 0.1 and 0.2 ms stimulus pulse widths. STEPIX was further applied to process CMAP scans of the FDI muscle from 13 tetraplegia and 13 healthy control subjects using the same stimulation parameter setting (0.1 ms, 500 stimuli), along with other methods including MScanFit motor unit number estimation (MUNE) and D50. STEPIX was significantly lower for the SCI subjects compared with the healthy control subjects. STEPIX was significantly correlated with MscanFit MUNE and D50, but had a smaller relative width of the overlapping zone (WOZ%) between tetraplegic and healthy control groups compared with MScanFit MUNE and D50. The findings of the study highlight the importance of maintaining a consistent stimulation parameter setting in CMAP scan studies and confirm the usefulness of STEPIX as a convenient CMAP scan parameter for examination of motor unit number changes.

Lack of Sod1 induces disruption of innervation accompanied by Schwann cell proliferation in skeletal muscle

The neuromuscular junction (NMJ) is an excitatory synapse that constitutes the primary site of communication between the nervous system and skeletal muscle and therefore any degenerative changes at the NMJ have the potential to impair muscle function. The primary cellular components of the NMJ are the motor neuron, the muscle fiber and terminal Schwann cells (tSC) that surround the NMJ. The importance of redox homeostasis for the maintenance of NMJ integrity is supported by work from our group showing degenerative changes at NMJs in mice lacking copper zinc superoxide dismutase (CuZnSOD; Sod1 -/- ) as early as 4 months of age. Prior work from others suggests that tSCs contribute trophic support for the NMJ and facilitate motor unit remodeling, but changes in tSC structure and function under conditions of elevated oxidative stress have not been thoroughly explored. Using in vitro assays, we previously showed that primary Schwann cells treated with a sublethal dose of the reactive oxygen species inducing agent Paraquat (PQ) resulted in increased Schwann cell number, ki67+ staining, and gene expression of trophic factors and the critical NMJ organizing protein Agrin. Furthermore, differentiated C2C12 myotubes treated with conditioned media from PQ treated Schwann cell cultures showed increased number of acetylcholine receptor (AChR) plaques. The goal of the current study was to characterize NMJs in young Sod1 -/- mice (2-months) to determine the early effects of elevated oxidative stress on NMJ structure in vivo with a specific focus on tSCs. We hypothesized that loss of Sod1 would lead to aberrant tSC and NMJ structure associated with decreased muscle function. We assessed maximum isometric force, NMJ morphology, and number of Schwann cells in gastrocnemius muscles of WT (n = 3) and Sod1 -/- (n = 3) mice. In Sod1 -/- mice, muscle force was reduced by 26% ( p = 2e-4) with nerve stimulation compared to direct muscle stimulation, and overlap between motor nerve terminals and AChRs was reduced by nearly 60% compared to WT controls. Post-synaptic AChR area was increased by 37% in Sod1 -/- mice, and tSC area and numbers per NMJ were increased by 60% and 155%, respectively in Sod1 -/- mice. Finally, Schwann cells proximal to NMJs showed increased Ki67+ labeling in Sod1 -/- mice compared to WT mice. This analysis demonstrates that early changes in both pre- and post-synaptic NMJ components and reduced neurotransmission due to loss of Sod1 are associated with marked increases in tSC proliferation. Our data implicate a protective role of muscle-resident Schwann cells in preserving NMJ integrity in response to alterations in redox homeostasis that may be mediated in part through activation and proliferation of these cells. These findings indicate that further investigation of the dynamics between Schwann cells and NMJ function is important to increase understanding of neuromuscular degenerativeconditions that involve altered redox homeostasis such as sarcopenia. Supported by the University of Michigan Medical School Office of Research, the American Physiological Society, and NIH AR069620. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Neurophysiological Hallmarks of Axonal Degeneration in CIDP Patients: A Pilot Analysis.

In this work, we aim to identify sensitive neurophysiological biomarkers of axonal degeneration in CIDP patients. A total of 16 CIDP patients, fulfilling the clinical and neurophysiological criteria for typical CIDP, treated with subcutaneous immunoglobulin (ScIg) (0.4 g/kg/week) were evaluated at baseline (before ScIg treatment) and after long-term treatment with ScIg (24 months) by clinical assessment scales, nerve conduction studies (NCS) and electromyography (EMG). Conventional and non-conventional neurophysiological parameters: motor unit potential (MUP) analysis, MUP thickness and size index (SI)] and interference pattern (IP) features were evaluated after long-term treatment (24 months) and compared with a population of 16 healthy controls (HC). An increase of distal motor latency (DML) and reduced compound motor action potential (CMAP) amplitude and area in CIDP patients suggest axonal damage of motor fibers, together with a significant increase of MUP amplitude, duration and area. Analysis of non-conventional MUP parameters shows no difference for MUP thickness; however, in CIDP patients, SI is increased and IP area and amplitude values are lower than HC. Despite clinical and neurophysiological improvement after ScIg treatment, neurophysiological analysis revealed axonal degeneration of motor fibers and motor unit remodeling. Correlation analysis shows that the axonal degeneration process is related to the diagnostic and therapeutic delay. MUP area and SI parameters can detect early signs of axonal degeneration, and their introduction in clinical practice may help to identify patients with the worst outcome.

Changes in neuromuscular function in elders: Novel techniques for assessment of motor unit loss and motor unit remodeling with aging

Functional muscle fiber denervation is a major contributor to the decline in physical function observed with aging and is now a recognized cause of sarcopenia, a muscle disorder characterized by progressive and generalized degenerative loss of skeletal muscle mass, quality, and strength. There is an interrelationship between muscle strength, motor unit (MU) number, and aging, which suggests that a portion of muscle weakness in seniors may be attributable to the loss of functional MUs. During normal aging, there is a time-related progression of MU loss, an adaptive sprouting followed by a maladaptive sprouting, and continuing recession of terminal Schwann cells leading to a reduced capacity for compensatory reinnervation in elders. In amyotrophic lateral sclerosis, increasing age at onset predicts worse survival ALS and it is possible that age-related depletion of the motor neuron pool may worsen motor neuron disease. MUNE methods are used to estimate the number of functional MU, data from MUNIX arguing for motor neuron loss with aging will be reviewed. Recently, a new MRI technique MU-MRI could be used to assess the MU recruitment or explore the activity of a single MU. This review presents published studies on the changes of neuromuscular function with aging, then focusing on these two novel techniques for assessment of MU loss and MU remodeling.

Ageing and exercise-induced motor unit remodelling.

A motor unit (MU) comprises the neuron cell body, its corresponding axon and each of the muscle fibres it innervates. Many studies highlight age‐related reductions in the number of MUs, yet the ability of a MU to undergo remodelling and to expand to rescue denervated muscle fibres is also a defining feature of MU plasticity. Remodelling of MUs involves two coordinated processes: (i) axonal sprouting and new branching growth from adjacent surviving neurons, and (ii) the formation of key structures around the neuromuscular junction to resume muscle–nerve communication. These processes rely on neurotrophins and coordinated signalling in muscle–nerve interactions. To date, several neurotrophins have attracted focus in animal models, including brain‐derived neurotrophic factor and insulin‐like growth factors I and II. Exercise in older age has demonstrated benefits in multiple physiological systems including skeletal muscle, yet evidence suggests this may also extend to peripheral MU remodelling. There is, however, a lack of research in humans due to methodological limitations which are easily surmountable in animal models. To improve mechanistic insight of the effects of exercise on MU remodelling with advancing age, future research should focus on combining methodological approaches to explore the in vivo physiological function of the MU alongside alterations of the localised molecular environment.

Alterations in Muscle Force Control With Aging: Is There a Modulatory Effect of Lifelong Physical Activity?

Recent technological developments have enabled significant advances in our understanding of the ability to voluntarily control muscle force output. The fluctuations inherent to muscle force output can be quantified according to both their magnitude and temporal structure (or “complexity”), with such quantification facilitating comparison of force control between distinct populations. In comparison to young adults, older adults exhibit an increase in the magnitude (i.e., decreased steadiness) and a decrease in the complexity (i.e., decreased adaptability) of force fluctuations, both of which are indicative of a loss of force control. There remain, however, key gaps in knowledge that limit our interpretation of this age-related loss of force control. One such gap relates to the effect of lifelong physical activity on force control. To date, research on aging and force control has largely been conducted on inactive or moderately active older adults. However, high levels of lifelong physical activity, such as that exhibited by Masters athletes, have been shown to have protective effects on the function and morphology of the neuromuscular system. Some of these effects (e.g., on impaired inhibitory transmission in the motor cortex and on motor unit discharge rates) have the potential to attenuate the age-related loss of force control, while others (e.g., greater motor unit remodeling capacity) have the potential to worsen it. We therefore propose that, in order to progress our knowledge of the effects of aging on force control, future studies must consider the potential modulatory effect of lifelong physical activity.

Skeletal muscle transcriptomics identifies common pathways in nerve crush injury and ageing

Motor unit remodelling involving repeated denervation and re-innervation occurs throughout life. The efficiency of this process declines with age contributing to neuromuscular deficits. This study investigated differentially expressed genes (DEG) in muscle following peroneal nerve crush to model motor unit remodelling in C57BL/6 J mice. Muscle RNA was isolated at 3 days post-crush, RNA libraries were generated using poly-A selection, sequenced and analysed using gene ontology and pathway tools. Three hundred thirty-four DEG were found in quiescent muscle from (26mnth) old compared with (4-6mnth) adult mice and these same DEG were present in muscle from adult mice following nerve crush. Peroneal crush induced 7133 DEG in muscles of adult and 699 DEG in muscles from old mice, although only one DEG (ZCCHC17) was found when directly comparing nerve-crushed muscles from old and adult mice. This analysis revealed key differences in muscle responses which may underlie the diminished ability of old mice to repair following nerve injury.

Development and Preliminary Validation of an Electromyography-Scoring Protocol for the Assessment and Grading of Muscle Involvement in Patients With Juvenile Idiopathic Inflammatory Myopathies

IntroductionWe performed a pilot study in order to investigate the feasibility of an electromyography (EMG)-scoring protocol for the assessment of disease activity in juvenile idiopathic inflammatory myopathies (JIIM). MethodsChildren with JIIM followed up in a tertiary-level care center underwent standardized clinical, laboratory, and EMG assessment. An EMG-scoring protocol was devised by a consensus panel including a pediatric neurophysiologist and two pediatric rheumatologists, based on a combined score obtained as the sum of (1) the presence of denervation signs (fibrillation potentials) and (2) motor unit remodeling (mixed pattern of short- and long-duration motor unit action potentials). The EMG-scoring protocol was then validated following the Outcome Measures in Rheumatoid Arthritis Clinical Trials filter for outcome measures in rheumatology and the consensus-based standards for the selection of health measurement instruments methodology. ResultsThirteen children (77% females) were included in the study, with a median age of 10 years (interquartile range: 7-17 years) and median disease duration of 11.8 months (interquartile range: 2.1-44.5). A total of 39 EMG examinations were evaluated. A strong positive association between a standardized tool for muscle strength assessment and the combined score was observed. No significant associations were found with both creatine kinase and erythrocyte sedimentation rate levels. DiscussionOur EMG-scoring protocol is the first standardized and reproducible tool for the neurophysiologic evaluation and grading of muscle involvement in patients with JIIM and could provide relevant additional information in the assessment and follow-up of these rare conditions.

Effect Of Age On High-velocity Power And Myofiber Morphology And Composition

Muscle power, or torque multiplied by velocity, is an important determinant of physical functioning in older adults. The ability to produce power is diminished in older adults compared to younger adults, especially at higher contraction velocities. It has been suggested that this may reflect age-related changes in single myofiber morphology and/or composition. PURPOSE: To examine power, muscle activation, and single myofiber morphology and composition in young (YM) and older (OM) males. METHODS: Power was recorded during isokinetic knee extensions at 60 deg/sec and 180 deg/sec in healthy, untrained YM (n = 15; 20.7 ± 2.2 yrs) and OM (n = 15; 71.6 ± 3.9 yrs). The relative increase in power from 60 deg/sec to 180 deg/sec was recorded for each participant. Electromyography amplitude of the vastus lateralis was normalized to its peak from a maximal isometric contraction to calculate muscle activation. Vastus lateralis tissue samples were obtained from a sub-sample (YM = 13; OM = 11) via microbiopsy and immunofluorescence was used to identify type I and IIa myofibers for subsequent analysis of cross-sectional area (CSA). Independent samples t-tests were used to compare groups and select correlations were assessed. RESULTS: Relative increase in power was greater in YM (159% vs. 115%; p = 0.005). Muscle activation was similar between groups (p > 0.05). The average number of myofibers analyzed per participant was similar between groups (YM = 562.3 ± 280.3, OM = 576.6 ± 201.4; p > 0.05). Individual fiber type composition and CSA were similar between groups (p > 0.05), but type IIa:type I myofiber size ratio was lower in OM (-31.15%; p = 0.002). Neither myofiber size nor composition data correlated with the relative power increase (p > 0.05). CONCLUSIONS: OM had smaller type IIa myofibers relative to type I myofiber size, which may reflect age-related motor unit remodeling. Nevertheless, neither myofiber size nor composition were associated with the age-related diminishment in relative power increase. These data indicate that factors other than myofiber size or composition may be responsible for the impaired ability to increase power at a higher velocity in OM, but our smaller sample size is an important consideration.

Influence of sex on the age-related adaptations of neuromuscular function and motor unit properties in elite masters athletes.

Masters athletes maintain high levels of activity into older age and allow an examination of the effects of aging dissociated from the effects of increased sedentary behaviour. Evidence suggests masters athletes are more successful at motor unit remodelling, the reinnervation of denervated fibres acting to preserve muscle fibre number, but little data are available in females. Here we used intramuscular electromyography to demonstrate that motor units sampled from the tibialis anterior show indications of remodelling from middle into older age and which does not differ between males and females. The age-related trajectory of motor unit discharge characteristic differs according to sex, with female athletes progressing to a slower firing pattern that was not observed in males. Our findings indicate motor unit remodelling from middle to older age occurs to a similar extent in male and female athletes, with discharge rates progressively slowing in females only. Motor unit (MU) remodelling acts to minimise loss of muscle fibres following denervation in older age, which may be more successful in masters athletes. Evidence suggests performance and neuromuscular function decline with age in this population, although the majority of studies have focused on males, with little available data on female athletes. Functional assessments of strength, balance and motor control were performed in 30 masters athletes (16 male) aged 44-83years. Intramuscular needle electrodes were used to sample individual motor unit potentials (MUPs) and near-fibre MUPs in the tibialis anterior (TA) during isometric contractions at 25% maximum voluntary contraction, and used to determine discharge characteristics (firing rate, variability) and biomarkers of peripheral MU remodelling (MUP size, complexity, stability). Multilevel mixed-effects linear regression models examined effects of age and sex. All aspects of neuromuscular function deteriorated with age (P<0.05) with no age×sex interactions, although males were stronger (P<0.001). Indicators of MU remodelling also progressively increased with age to a similar extent in both sexes (P<0.05), whilst MU firing rate progressively decreased with age in females (p=0.029), with a non-significant increase in males (p=0.092). Masters athletes exhibit age-related declines in neuromuscular function that are largely equal across males and females. Notably, they also display features of MU remodelling with advancing age, probably acting to reduce muscle fibre loss. The age trajectory of MU firing rate assessed at a single contraction level differed between sexes, which may reflect a greater tendency for females to develop a slower muscle phenotype.

Absence of an aging‐related increase in fiber type grouping in athletes and non‐athletes

The aging-related loss of muscle mass is thought to be partly attributable to motor neuron loss and motor unit remodeling that result in fiber type grouping. We examined fiber type grouping in 19- to 85-year-old athletes and non-athletes and evaluated to which extent any observed grouping is explained by the fiber type composition of the muscle. Since regular physical activity may stimulate reinnervation, we hypothesized that fiber groups are larger in master athletes than in age-matched non-athletes. Fiber type grouping was assessed in m. vastus lateralis biopsies from 22 young (19-27years) and 35 healthy older (66-82years) non-athletes, and 14 young (20-29years), 51 middle-aged (38-65years), and 31 older (66-85years) athletes. An "enclosed fiber" was any muscle fiber of a particular type surrounded by fibers of the same type only. A fiber type group was defined as a group of fibers with at least one enclosed fiber. Only type II fiber cross-sectional area (FCSA) showed an age-related decline that was greater in athletes (P<.001) than in non-athletes (P=.012). There was no significant age-related effect on fiber group size or fiber group number in athletes or non-athletes, and the observed grouping was similar to that expected from the fiber type composition. At face value, these observations do 1) neither show evidence for an age-related loss and remodeling of motor units nor 2) improved reinnervation with regular physical activity, but 3) histological examination may not reveal the full extent of aging-related motor unit remodeling.

Head-down tilt bed rest with or without artificial gravity is not associated with motor unit remodeling

PurposeThe objective of this study was to assess whether artificial gravity attenuates any long-duration head-down 60 bed rest (HDBR)-induced alterations in motor unit (MU) properties.MethodsTwenty-four healthy participants (16 men; 8 women; 26–54 years) underwent 60-day HDBR with (n = 16) or without (n = 8) 30 min artificial gravity daily induced by whole-body centrifugation. Compound muscle action potential (CMAP), MU number (MUNIX) and MU size (MUSIX) were estimated using the method of Motor Unit Number Index in the Abductor digiti minimi and tibialis anterior muscles 5 days before (BDC-5), and during day 4 (HDT4) and 59 (HDT59) of HDBR.ResultsThe CMAP, MUNIX, and MUSIX at baseline did not change significantly in either muscle, irrespective of the intervention (p > 0.05). Across groups, there were no significant differences in any variable during HDBR, compared to BDC-5.ConclusionSixty days of HDBR with or without artificial gravity does not induce alterations in motor unit number and size in the ADM or TA muscles in healthy individuals.

Causes of, and countermeasures to, increased ventilatory drive in tetraplegia.

Causes of, and countermeasures to, increased ventilatory drive in tetraplegia.

Increased diaphragm motor unit discharge frequencies during quiet breathing in people with chronic tetraplegia.

Respiratory muscle strength is compromised in people with tetraplegia, which may be compensated for by an increase in neural drive to the diaphragm. We found that the discharge frequencies of diaphragm motor units are higher in people with chronic tetraplegia compared with able-bodied people during quiet breathing. Furthermore, we found that the area of single motor unit potentials was increased in people with tetraplegia. These results suggest an increased motoneurone output to the diaphragm and remodelling of diaphragm motor units to maintain ventilation in tetraplegia. People with tetraplegia have reduced inspiratory muscle strength, ∼40% of able-bodied individuals. Paralysed or partially paralysed respiratory muscles as a result of tetraplegia compromise lung function, increase the incidence of respiratory infections and can cause dyspnoea. We hypothesised that reduced inspiratory muscle strength in tetraplegia may increase neural drive to the inspiratory muscles to maintain ventilation. We recorded the discharge properties of single motor units from the diaphragm in participants with chronic tetraplegia (8 males, 42-78 years, C3-C6 injury, AIS A-C) and able-bodied control participants (6 males matched for age and body mass index). In each group, 117 and 166 single motor units, respectively, were discriminated from recordings in the costal diaphragm using a monopolar electrode. A linear mixed-effects model analysis showed higher peak discharge frequencies of motor units during quiet breathing in tetraplegia (17.8 ± 4.9Hz; mean ± SD) compared with controls (12.4 ± 2.2Hz) (P < 0.001). There were no differences in tidal volume, inspiratory time or mean air flow between groups. Motor unit potentials in tetraplegia, compared with controls, were larger in amplitude (1.1 ± 0.7mV and 0.5 ± 0.3mV, respectively, P = 0.007) and area (1.83 ± 1.49µV ms and 0.69 ± 0.52µV ms, respectively, P = 0.003). The findings indicate that diaphragm motor unit remodelling is likely to have occurred in people with chronic tetraplegia and that there is an increase in diaphragm motor unit discharge rates during quiet breathing. These neural changes ensure that ventilation is maintained in people with chronic tetraplegia.

Sex-Specific Differences in Motor-Unit Remodeling in a Mouse Model of ALS.

Progressive loss of neuromuscular junctions (NMJs) is an early event in amyotrophic lateral sclerosis (ALS), preceding the global degeneration of motor axons and being accompanied by new axonal sprouting within the same axonal arbor. Some aspects of ALS onset and progression seem to be affected by sex in animal models of the disease. However, whether there are sex-specific differences in the pattern or time course of NMJ loss and repair within single motor axons remains unknown. We performed further analysis of a previously published in vivo dataset, obtained from male and female SOD1G37R mice. We found that NMJ losses are as frequent in male and female motor axons but, intriguingly, axonal sprouting is more frequent in female than male mice, resulting in a net increase of axonal arborization. Interestingly, these numerous new axonal branches in female mice are associated with a slightly faster decline in grip strength, increased NMJ denervation, and reduced α-motor neuron survival. Collectively, these results suggest that excessive axonal sprouting and motor-unit (MU) expansion in female SOD1G37R mice are maladaptive during ALS progression.

A micromechanical muscle model for determining the impact of motor unit fiber clustering on force transmission in aging skeletal muscle

This study used a micromechanical finite element muscle model to investigate the effects of the redistribution of spatial activation patterns in young and old muscle. The geometry consisted of a bundle of 19 active muscle fibers encased in endomysium sheets, surrounded by passive tissue to model a fascicle. Force was induced by activating combinations of the 19 active muscle fibers. The spacial clustering of muscle fibers modeled in this study showed unbalanced strains suggesting tissue damage at higher strain levels may occur during higher levels of activation and/or during dynamic conditions. These patterns of motor unit remodeling are one of the consequences of motor unit loss and reinnervation associated with aging. The results did not reveal evident quantitative changes in force transmission between old and young adults, but the patterns of stress and strain distribution were affected, suggesting an uneven distribution of the forces may occur within the fascicle that could provide a mechanism for muscle injury in older muscle.

Genomic profiling using RNAseq to identify key drivers of sarcopenia and motor unit turnover in murine skeletal muscle

Sarcopenia; the age‐related loss of skeletal muscle mass and function, significantly affects quality of life in the aging population and has been linked to remodelling and loss of motor units. Throughout the life course, there is evidence for motor unit turnover through cycles of denervation and reinnervation of individual muscle fibres and at more advanced ages this process may breakdown. The mechanisms that underlie these processes are unclear, but are believed to be multifactorial which has confounded efforts to identify primary mechanisms.The aim of this study was to determine the gene expression profiles in the anterior tibialis muscle of adult (6–8 months) and old (26 months) mice before and 3 days after peroneal nerve crush surgery. We achieved this with RNA deep sequencing and parallel histological, molecular and electrophysiological assessments of muscle pathophysiology.Nerve crush injury was used to mimic motor unit remodelling at the neuromuscular junctions since the crush injury damages all axons, but the endoneurial tubes are preserved which alongside the Schwann cell basal laminae which remains, enables axonal elongation and facilitates reinnervation. Samples were examined at 3 days post‐crush since this at time point there was complete loss of pre‐synaptic input to the neuromuscular junctions and hence putatively a time when sprouting factors and nerve regenerative proteins are being transcribed. Using paired‐end 2×75 base pair sequencing we generated data from &gt;280 M clusters per lane (n=5/treatment).In total, 16 differentially expressed genes (DEGs) were found in the AT muscle in response to age. 1448 DEGs were changed in the muscle of adult mice in response to nerve crush in comparison with 644 DEGs identified in the muscle of old mice in response to nerve crush.The protein coding DEG (adjusted for by False Discovery Rate &lt;0.05 and 1.4log2 fold change) were then examined and those with highest and lowest fold changes from each treatment contrasts were investigated using DAVID and Ingenuity Pathway Analysis (IPA) to reveal key upstream regulators as well as canonical pathways for each contrast. Several DEGs were revealed across the different contrasts and of particular interest ZCCHC17 (previously reported as a master regulator of synaptic gene expression in Alzheimer's disease) was altered with age in response to crush. Key pathways affected by aging and nerve crush included P13K‐Akt signalling, NFkB signalling, Schwann cell guidance, axonal guidance and extension.These findings provide a novel insight into the effects of aging on the response of muscle to nerve crush. Further studies are underway to identify the specific signalling pathways involved. These results reveal potential therapeutic targets that could aid the regenerative capacity of aging skeletal muscle.Support or Funding InformationThis work was funded by the UK Medical Research Council.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.