Myasthenia Gravis: Analysis of Serum Autoantibody Reactivities to 1827 Potential Human Autoantigens by Protein Macroarrays

Background

Myasthenia gravis is a disorder of neuromuscular transmission associated with autoantibodies against the nicotinic acetylcholine receptor. We have previously developed a customized protein macroarray comprising 1827 potential human autoantigens, which permitted to discriminate sera of patients with different cancers from sera of healthy controls, but has not yet been evaluated in antibody-mediated autoimmune diseases.

Objective

To determine whether autoantibody signatures obtained by protein macroarray separate sera of patients with myasthenia gravis from healthy controls.

Methods

Sera of patients with acetylcholine receptor antibody-positive myasthenia gravis (n = 25) and healthy controls (n = 32) were analyzed by protein macroarrays comprising 1827 peptide clones.

Results

Autoantibody signatures did not separate patients with myasthenia gravis from controls with sufficient sensitivity, specificity, and accuracy. Intensity values of one antigen (poly A binding protein cytoplasmic 1, p = 0.0045) were higher in patients with myasthenia gravis, but the relevance of this and two further antigens, 40S ribosomal protein S13 (20.8% vs. 0%, p = 0.011) and proteasome subunit alpha type 1 (25% vs. 3.1%, p = 0.035), which were detected more frequently by myasthenia gravis than by control sera, currently remains uncertain.

Conclusion

Seroreactivity profiles of patients with myasthenia gravis detected by a customized protein macroarray did not allow discrimination from healthy controls, compatible with the notion that the autoantibody response in myasthenia gravis is highly focussed against the acetylcholine receptor.     

The Function of Cortactin in the Clustering of Acetylcholine Receptors at the Vertebrate Neuromuscular Junction

Background

Postsynaptic enrichment of acetylcholine receptors (AChRs) at the vertebrate neuromuscular junction (NMJ) depends on the activation of the muscle receptor tyrosine MuSK by neural agrin. Agrin-stimulation of MuSK is known to initiate an intracellular signaling cascade that leads to the clustering of AChRs in an actin polymerization-dependent manner, but the molecular steps which link MuSK activation to AChR aggregation remain incompletely defined.

Methodology/Principal Findings

In this study we used biochemical, cell biological and molecular assays to investigate a possible role in AChR clustering of cortactin, a protein which is a tyrosine kinase substrate and a regulator of F-actin assembly and which has also been previously localized at AChR clustering sites. We report that cortactin was co-enriched at AChR clusters in situ with its target the Arp2/3 complex, which is a key stimulator of actin polymerization in cells. Cortactin was further preferentially tyrosine phosphorylated at AChR clustering sites and treatment of myotubes with agrin significantly enhanced the tyrosine phosphorylation of cortactin. Importantly, forced expression in myotubes of a tyrosine phosphorylation-defective cortactin mutant (but not wild-type cortactin) suppressed agrin-dependent AChR clustering, as did the reduction of endogenous cortactin levels using RNA interference, and introduction of the mutant cortactin into muscle cells potently inhibited synaptic AChR aggregation in response to innervation.

Conclusion

Our results suggest a novel function of phosphorylation-dependent cortactin signaling downstream from agrin/MuSK in facilitating AChR clustering at the developing NMJ.     

Participation of myosin Va and Pka type I in the regeneration of neuromuscular junctions

Background

The unconventional motor protein, myosin Va, is crucial for the development of the mouse neuromuscular junction (NMJ) in the early postnatal phase. Furthermore, the cooperative action of protein kinase A (PKA) and myosin Va is essential to maintain the adult NMJ. We here assessed the involvement of myosin Va and PKA in NMJ recovery during muscle regeneration.

Methodology/Principal Findings

To address a putative role of myosin Va and PKA in the process of muscle regeneration, we used two experimental models the dystrophic mdx mouse and Notexin-induced muscle degeneration/regeneration. We found that in both systems myosin Va and PKA type I accumulate beneath the NMJs in a fiber maturation-dependent manner. Morphologically intact NMJs were found to express stable nicotinic acetylcholine receptors and to accumulate myosin Va and PKA type I in the subsynaptic region. Subsynaptic cAMP signaling was strongly altered in dystrophic muscle, particularly in fibers with severely subverted NMJ morphology.

Conclusions/Significance

Our data show a correlation between the subsynaptic accumulation of myosin Va and PKA type I on the one hand and NMJ regeneration status and morphology, AChR stability and specificity of subsynaptic cAMP handling on the other hand. This suggests an important role of myosin Va and PKA type I for the maturation of NMJs in regenerating muscle.     

Role of Myosin Va in the Plasticity of the Vertebrate Neuromuscular Junction In Vivo

Background

Myosin Va is a motor protein involved in vesicular transport and its absence leads to movement disorders in humans (Griscelli and Elejalde syndromes) and rodents (e.g. dilute lethal phenotype in mice). We examined the role of myosin Va in the postsynaptic plasticity of the vertebrate neuromuscular junction (NMJ).

Methodology/Principal Findings

Dilute lethal mice showed a good correlation between the propensity for seizures, and fragmentation and size reduction of NMJs. In an aneural C2C12 myoblast cell culture, expression of a dominant-negative fragment of myosin Va led to the accumulation of punctate structures containing the NMJ marker protein, rapsyn-GFP, in perinuclear clusters. In mouse hindlimb muscle, endogenous myosin Va co-precipitated with surface-exposed or internalised acetylcholine receptors and was markedly enriched in close proximity to the NMJ upon immunofluorescence. In vivo microscopy of exogenous full length myosin Va as well as a cargo-binding fragment of myosin Va showed localisation to the NMJ in wildtype mouse muscles. Furthermore, local interference with myosin Va function in live wildtype mouse muscles led to fragmentation and size reduction of NMJs, exclusion of rapsyn-GFP from NMJs, reduced persistence of acetylcholine receptors in NMJs and an increased amount of punctate structures bearing internalised NMJ proteins.

Conclusions/Significance

In summary, our data show a crucial role of myosin Va for the plasticity of live vertebrate neuromuscular junctions and suggest its involvement in the recycling of internalised acetylcholine receptors back to the postsynaptic membrane.     

Meltrin β/ADAM19 Interacting with EphA4 in Developing Neural Cells Participates in Formation of the Neuromuscular Junction

Background

Development of the neuromuscular junction (NMJ) is initiated by the formation of postsynaptic specializations in the central zones of muscles, followed by the arrival of motor nerve terminals opposite the postsynaptic regions. The post- and presynaptic components are then stabilized and modified to form mature synapses. Roles of ADAM (A Disintegrin And Metalloprotease) family proteins in the formation of the NMJ have not been reported previously.

Principal Findings

We report here that Meltrin β, ADAM19, participates in the formation of the NMJ. The zone of acetylcholine receptor α mRNA distribution was broader and excess sprouting of motor nerve terminals was more prominent in meltrin β–deficient than in wild-type embryonic diaphragms. A microarray analysis revealed that the preferential distribution of ephrin-A5 mRNA in the synaptic region of muscles was aberrant in the meltrin β–deficient muscles. Excess sprouting of motor nerve terminals was also found in ephrin-A5 knockout mice, which lead us to investigate a possible link between Meltrin β and ephrin-A5-Eph signaling in the development of the NMJ. Meltrin β and EphA4 interacted with each other in developing motor neurons, and both of these proteins localized in the NMJ. Coexpression of Meltrin β and EphA4 strongly blocked vesicular internalization of ephrin-A5–EphA4 complexes without requiring the protease activity of Meltrin β, suggesting a regulatory role of Meltrin β in ephrin-A5-Eph signaling.

Conclusion

Meltrin β plays a regulatory role in formation of the NMJ. The endocytosis of ephrin-Eph complexes is required for efficient contact-dependent repulsion between ephrin and Eph. We propose that Meltrin β stabilizes the interaction between ephrin-A5 and EphA4 by regulating endocytosis of the ephrinA5-EphA complex negatively, which would contribute to the fine-tuning of the NMJ during development.     

Population based study of 12 autoimmune diseases in Sardinia, Italy: prevalence and comorbidity

Background

The limited availability of prevalence data based on a representative sample of the general population, and the limited number of diseases considered in studies about co-morbidity are the critical factors in study of autoimmune diseases. This paper describes the prevalence of 12 autoimmune diseases in a representative sample of the general population in the South of Sardinia, Italy, and tests the hypothesis of an overall association among these diseases.

Methods

Data were obtained from 21 GPs. The sample included 25,885 people. Prevalence data were expressed with 95% Poisson C.I. The hypothesis of an overall association between autoimmune diseases was tested by evaluating the co-occurrence within individuals.

Results

Prevalence per 100,000 are: 552 rheumatoid arthritis, 124 ulcerative colitis, 15 Crohn''s disease, 464 type 1 diabetes, 81 systemic lupus erythematosus, 124 celiac disease, 35 myasthenia gravis, 939 psoriasis/psoriatic arthritis, 35 systemic sclerosis, 224 multiple sclerosis, 31 Sjogren''s syndrome, and 2,619 autoimmune thyroiditis . An overall association between autoimmune disorders was highlighted.

Conclusions

The comparisons with prevalence reported in current literature do not show outlier values, except possibly for a few diseases like celiac disease and myasthenia gravis. People already affected by a first autoimmune disease have a higher probability of being affected by a second autoimmune disorder. In the present study, the sample size, together with the low overall prevalence of autoimmune diseases in the population, did not allow us to examine which diseases are most frequently associated with other autoimmune diseases. However, this paper makes available an adequate control population for future clinical studies aimed at exploring the co-morbidity of specific pairs of autoimmune diseases.     

Quantitative motor assessment of muscular weakness in myasthenia gravis: a pilot study

Background

Muscular weakness in myasthenia gravis (MG) is commonly assessed using Quantitative Myasthenia Gravis Score (QMG). More objective and quantitative measures may complement the use of clinical scales and might detect subclinical affection of muscles. We hypothesized that muscular weakness in patients with MG can be quantified with the non-invasive Quantitative Motor (Q-Motor) test for Grip Force Assessment (QGFA) and Involuntary Movement Assessment (QIMA) and that pathological findings correlate with disease severity as measured by QMG.

Methods

This was a cross-sectional pilot study investigating patients with confirmed diagnosis of MG. Data was compared to healthy controls (HC). Subjects were asked to lift a device (250 and 500 g) equipped with electromagnetic sensors that measured grip force (GF) and three-dimensional changes in position and orientation. These were used to calculate the position index (PI) and orientation index (OI) as measures for involuntary movements due to muscular weakness.

Results

Overall, 40 MG patients and 23 HC were included. PI and OI were significantly higher in MG patients for both weights in the dominant and non-dominant hand. Subgroup analysis revealed that patients with clinically ocular myasthenia gravis (OMG) also showed significantly higher values for PI and OI in both hands and for both weights. Disease severity correlates with QIMA performance in the non-dominant hand.

Conclusion

Q-Motor tests and particularly QIMA may be useful objective tools for measuring motor impairment in MG and seem to detect subclinical generalized motor signs in patients with OMG. Q-Motor parameters might serve as sensitive endpoints for clinical trials in MG.

     

Flow Cytofluorimetric Analysis of Anti-LRP4 (LDL Receptor-Related Protein 4) Autoantibodies in Italian Patients with Myasthenia Gravis

Background

Myasthenia gravis (MG) is an autoimmune disease in which 90% of patients have autoantibodies against the muscle nicotinic acetylcholine receptor (AChR), while autoantibodies to muscle-specific tyrosine kinase (MuSK) have been detected in half (5%) of the remaining 10%. Recently, the low-density lipoprotein receptor-related protein 4 (LRP4), identified as the agrin receptor, has been recognized as a third autoimmune target in a significant portion of the double sero-negative (dSN) myasthenic individuals, with variable frequency depending on different methods and origin countries of the tested population. There is also convincing experimental evidence that anti-LRP4 autoantibodies may cause MG.

Methods

The aim of this study was to test the presence and diagnostic significance of anti-LRP4 autoantibodies in an Italian population of 101 myasthenic patients (55 dSN, 23 AChR positive and 23 MuSK positive), 45 healthy blood donors and 40 patients with other neurological diseases as controls. All sera were analyzed by a cell-based antigen assay employing LRP4-transfected HEK293T cells, along with a flow cytofluorimetric detection system.

Results

We found a 14.5% (8/55) frequency of positivity in the dSN-MG group and a 13% frequency of co-occurrence (3/23) in both AChR and MuSK positive patients; moreover, we report a younger female prevalence with a mild form of disease in LRP4-positive dSN-MG individuals.

Conclusion

Our data confirm LRP4 as a new autoimmune target, supporting the value of including anti-LRP4 antibodies in further studies on Myasthenia gravis.     

Muscle Mitochondrial Uncoupling Dismantles Neuromuscular Junction and Triggers Distal Degeneration of Motor Neurons

Background

Amyotrophic lateral sclerosis (ALS), the most frequent adult onset motor neuron disease, is associated with hypermetabolism linked to defects in muscle mitochondrial energy metabolism such as ATP depletion and increased oxygen consumption. It remains unknown whether muscle abnormalities in energy metabolism are causally involved in the destruction of neuromuscular junction (NMJ) and subsequent motor neuron degeneration during ALS.

Methodology/Principal Findings

We studied transgenic mice with muscular overexpression of uncoupling protein 1 (UCP1), a potent mitochondrial uncoupler, as a model of muscle restricted hypermetabolism. These animals displayed age-dependent deterioration of the NMJ that correlated with progressive signs of denervation and a mild late-onset motor neuron pathology. NMJ regeneration and functional recovery were profoundly delayed following injury of the sciatic nerve and muscle mitochondrial uncoupling exacerbated the pathology of an ALS animal model.

Conclusions/Significance

These findings provide the proof of principle that a muscle restricted mitochondrial defect is sufficient to generate motor neuron degeneration and suggest that therapeutic strategies targeted at muscle metabolism might prove useful for motor neuron diseases.     

Inhibition of AMPK expression in skeletal muscle by systemic inflammation in COPD rats

Background

Chronic obstructive pulmonary disease (COPD) is a disease characterized by airflow limitation and inflammation. Meanwhile, COPD also is associated with metabolic disorders, such as skeletal muscle weakness. Strikingly, activation of AMP-activated protein kinase (AMPK) exerts critical roles in energy metabolism. However, it remains unclear whether and how the expression levels of AMPK are affected in the COPD model rats which may lead to the dysfunction of the skeletal muscle in these rats.

Methods

Here we developed a rat model of COPD, and we investigated the morphological changes of peripheral skeletal muscle and measured the levels of tumor necrosis factor -α (TNF-α) and AMPK in skeletal muscle by using approaches that include immunohistochemistry and polymerase chain reaction (PCR).

Results

We found that the expression levels of both AMPK mRNA and protein in skeletal muscles were significantly reduced in the COPD model rats, in comparison to those from the control rats, the COPD model rats that received treatments with AICAR and resveratrol, whereas the expression levels of TNF-α were elevated in COPD rats.

Conclusion

Such findings indicate that AMPK may serve as a target for therapeutic intervention in the treatment of muscle weakness in COPD patients.     

Muscle dystroglycan organizes the postsynapse and regulates presynaptic neurotransmitter release at the Drosophila neuromuscular junction

Background

The Dystrophin-glycoprotein complex (DGC) comprises dystrophin, dystroglycan, sarcoglycan, dystrobrevin and syntrophin subunits. In muscle fibers, it is thought to provide an essential mechanical link between the intracellular cytoskeleton and the extracellular matrix and to protect the sarcolemma during muscle contraction. Mutations affecting the DGC cause muscular dystrophies. Most members of the DGC are also concentrated at the neuromuscular junction (NMJ), where their deficiency is often associated with NMJ structural defects. Hence, synaptic dysfunction may also intervene in the pathology of dystrophic muscles. Dystroglycan is a central component of the DGC because it establishes a link between the extracellular matrix and Dystrophin. In this study, we focused on the synaptic role of Dystroglycan (Dg) in Drosophila.

Methodology/Principal Findings

We show that Dg was concentrated postsynaptically at the glutamatergic NMJ, where, like in vertebrates, it controls the concentration of synaptic Laminin and Dystrophin homologues. We also found that synaptic Dg controlled the amount of postsynaptic 4.1 protein Coracle and alpha-Spectrin, as well as the relative subunit composition of glutamate receptors. In addition, both Dystrophin and Coracle were required for normal Dg concentration at the synapse. In electrophysiological recordings, loss of postsynaptic Dg did not affect postsynaptic response, but, surprisingly, led to a decrease in glutamate release from the presynaptic site.

Conclusion/Significance

Altogether, our study illustrates a conservation of DGC composition and interactions between Drosophila and vertebrates at the synapse, highlights new proteins associated with this complex and suggests an unsuspected trans-synaptic function of Dg.     

Mechanism of acetylcholine receptor cluster formation induced by DC electric field

Background

The formation of acetylcholine receptor (AChR) cluster is a key event during the development of the neuromuscular junction. It is induced through the activation of muscle-specific kinase (MuSK) by the heparan-sulfate proteoglycan agrin released from the motor axon. On the other hand, DC electric field, a non-neuronal stimulus, is also highly effective in causing AChRs to cluster along the cathode-facing edge of muscle cells.

Methodology/Principal Findings

To understand its molecular mechanism, quantum dots (QDs) were used to follow the movement of AChRs as they became clustered under the influence of electric field. From analyses of trajectories of AChR movement in the membrane, it was concluded that diffuse receptors underwent Brownian motion until they were immobilized at sites of cluster formation. This supports the diffusion-mediated trapping model in explaining AChR clustering under the influence of this stimulus. Disrupting F-actin cytoskeleton assembly and interfering with rapsyn-AChR interaction suppressed this phenomenon, suggesting that these are integral components of the trapping mechanism induced by the electric field. Consistent with the idea that signaling pathways are activated by this stimulus, the localization of tyrosine-phosphorylated forms of AChR β-subunit and Src was observed at cathodal AChR clusters. Furthermore, disrupting MuSK activity through the expression of a kinase-dead form of this enzyme abolished electric field-induced AChR clustering.

Conclusions

These results suggest that DC electric field as a physical stimulus elicits molecular reactions in muscle cells in the form of cathodal MuSK activation in a ligand-free manner to trigger a signaling pathway that leads to cytoskeletal assembly and AChR clustering.     

Reciprocal Regulation of Axonal Filopodia and Outgrowth during Neuromuscular Junction Development

Background

The assembly of the vertebrate neuromuscular junction (NMJ) is initiated when nerve and muscle first contact each other by filopodial processes which are thought to enable close interactions between the synaptic partners and facilitate synaptogenesis. We recently reported that embryonic Xenopus spinal neurons preferentially extended filopodia towards cocultured muscle cells and that basic fibroblast growth factor (bFGF) produced by muscle activated neuronal FGF receptor 1 (FGFR1) to induce filopodia and favor synaptogenesis. Intriguingly, in an earlier study we found that neurotrophins (NTs), a different set of target-derived factors that act through Trk receptor tyrosine kinases, promoted neuronal growth but hindered presynaptic differentiation and NMJ formation. Thus, here we investigated how bFGF- and NT-signals in neurons jointly elicit presynaptic changes during the earliest stages of NMJ development.

Methodology/Principal Findings

Whereas forced expression of wild-type TrkB in neurons reduced filopodial extension and triggered axonal outgrowth, expression of a mutant TrkB lacking the intracellular kinase domain enhanced filopodial growth and slowed axonal advance. Neurons overexpressing wild-type FGFR1 also displayed more filopodia than control neurons, in accord with our previous findings, and, notably, this elevation in filopodial density was suppressed when neurons were chronically treated from the beginning of the culture period with BDNF, the NT that specifically activates TrkB. Conversely, inhibition by BDNF of NMJ formation in nerve-muscle cocultures was partly reversed by the overexpression of bFGF in muscle.

Conclusions

Our results suggest that the balance between neuronal FGFR1- and TrkB-dependent filopodial assembly and axonal outgrowth regulates the establishment of incipient NMJs.     

The Study of Intramuscular Nerve Distribution Patterns and Relative Spindle Abundance of the Thenar and Hypothenar Muscles in Human Hand

Background

The intramuscular nerve distribution and relative spindle abundance of the human hand have not been well defined, although this is important in guiding hand surgery.

Methods

Forty human hands were dissected and subjected to modified Sihler’s stain and haematoxylin and eosin stain to investigate intramuscular nerve distribution and relative spindle abundance, respectively.

Results

The flexor pollicis brevis (FPB), adductor pollicis (AP), and abductor digiti minimi (ADM) contain separate nerve compartments. Neural anastomoses were observed in the thenar and hypothenar muscles, including the Y-like, O-like, H-like, and U-like appearance. We found that U-like neural anastomoses may be the characteristic of the opponens muscles. The relative spindle abundance was the greatest in the opponens muscles which may coordinate fine movements.

Conclusion

Except for the two opponens muscles, the rest of the thenar and hypothenar muscles could be used as whole muscle or half-muscle donors for muscle transplant. Our nerve map of the hand offers valuable guidance for hand reconstruction.     

Age- and Gender-Related Changes in Contractile Properties of Non-Atrophied EDL Muscle

Background

In humans, ageing causes skeletal muscles to become atrophied, weak, and easily fatigued. In rodent studies, ageing has been associated with significant muscle atrophy and changes in the contractile properties of the muscles. However, it is not entirely clear whether these changes in contractile properties can occur before there is significant atrophy, and whether males and females are affected differently.

Methods and Results

We investigated various contractile properties of whole isolated fast-twitch EDL muscles from adult (2–6 months-old) and aged (12–22 months-old) male and female mice. Atrophy was not present in the aged mice. Compared with adult mice, EDL muscles of aged mice had significantly lower specific force, longer tetanus relaxation times, and lower fatiguability. In the properties of absolute force and muscle relaxation times, females were affected by ageing to a greater extent than males. Additionally, EDL muscles from a separate group of male mice were subjected to eccentric contractions of 15% strain, and larger force deficits were found in aged than in adult mice.

Conclusion

Our findings provide further insight into the muscle atrophy, weakness and fatiguability experienced by the elderly. We have shown that even in the absence of muscle atrophy, there are definite alterations in the physiological properties of whole fast-twitch muscle from ageing mice, and for some of these properties the alterations are more pronounced in female mice than in male mice.     

Impaired skeletal muscle microcirculation in systemic sclerosis

Introduction

Muscle symptoms in systemic sclerosis (SSc) may originate from altered skeletal muscle microcirculation, which can be investigated by means of blood oxygenation level dependent (BOLD) magnetic resonance imaging (MRI).

Methods

After ethics committee approval and written consent, 11 consecutive SSc patients (5 men, mean age 52.6 years, mean SSc disease duration 5.4 years) and 12 healthy volunteers (4 men, mean age 45.1 years) were included. Subjects with peripheral arterial occlusive disease were excluded. BOLD MRI was performed on calf muscles during cuff-induced ischemia and reactive hyperemia, using a 3-T whole-body scanner (Verio, Siemens, Erlangen, Germany) and fat-suppressed single-short multi-echo echo planar imaging (EPI) with four different effective echo times. Muscle BOLD signal time courses were obtained for gastrocnemius and soleus muscles: minimal hemoglobin oxygen saturation (T2*_min) and maximal T2* values (T2*_max), time to T2* peak (TTP), and slopes of oxygen normalization after T2* peaking.

Results

The vast majority of SSc patients lacked skeletal muscle atrophy, weakness or serum creatine kinase elevation. Nevertheless, more intense oxygen desaturation during ischemia was observed in calf muscles of SSc patients (mean T2*_min -15.0%), compared with controls (-9.1%, P = 0.02). SSc patients also had impaired oxygenation during hyperemia (median T2*_max 9.2% vs. 20.1%, respectively, P = 0.007). The slope of muscle oxygen normalization was significantly less steep and prolonged (TTP) in SSc patients (P<0.001 for both). Similar differences were found at a separate analysis of gastrocnemius and soleus muscles, with most pronounced impairment in the gastrocnemius.

Conclusions

BOLD MRI demonstrates a significant impairment of skeletal muscle microcirculation in SSc.     

Proprioceptive Changes Impair Balance Control in Individuals with Chronic Obstructive Pulmonary Disease

Introduction

Balance deficits are identified as important risk factors for falling in individuals with chronic obstructive pulmonary disease (COPD). However, the specific use of proprioception, which is of primary importance during balance control, has not been studied in individuals with COPD. The objective was to determine the specific proprioceptive control strategy during postural balance in individuals with COPD and healthy controls, and to assess whether this was related to inspiratory muscle weakness.

Methods

Center of pressure displacement was determined in 20 individuals with COPD and 20 age/gender-matched controls during upright stance on an unstable support surface without vision. Ankle and back muscle vibration were applied to evaluate the relative contribution of different proprioceptive signals used in postural control.

Results

Individuals with COPD showed an increased anterior-posterior body sway during upright stance (p = 0.037). Compared to controls, individuals with COPD showed an increased posterior body sway during ankle muscle vibration (p = 0.047), decreased anterior body sway during back muscle vibration (p = 0.025), and increased posterior body sway during simultaneous ankle-muscle vibration (p = 0.002). Individuals with COPD with the weakest inspiratory muscles showed the greatest reliance on ankle muscle input when compared to the stronger individuals with COPD (p = 0.037).

Conclusions

Individuals with COPD, especially those with inspiratory muscle weakness, increased their reliance on ankle muscle proprioceptive signals and decreased their reliance on back muscle proprioceptive signals during balance control, resulting in a decreased postural stability compared to healthy controls. These proprioceptive changes may be due to an impaired postural contribution of the inspiratory muscles to trunk stability. Further research is required to determine whether interventions such as proprioceptive training and inspiratory muscle training improve postural balance and reduce the fall risk in individuals with COPD.     

Quadriceps arthrogenic muscle inhibition: the effects of experimental knee joint effusion on motor cortex excitability

Introduction

Marked weakness of the quadriceps muscles is typically observed following injury, surgery or pathology affecting the knee joint. This is partly due to ongoing neural inhibition that prevents the central nervous system from fully activating the quadriceps, a process known as arthrogenic muscle inhibition (AMI). This study aimed to further investigate the mechanisms underlying AMI by exploring the effects of experimental knee joint effusion on quadriceps corticomotor and intracortical excitability.

Methods

Seventeen healthy volunteers participated in this study. Transcranial magnetic stimulation was used to measure quadriceps motor evoked potential area, short-interval intracortical inhibition, intracortical facilitation and cortical silent period duration before and after experimental knee joint effusion. Joint effusion was induced by the intraarticular infusion of dextrose saline into the knee.

Results

There was a significant increase in quadriceps motor evoked potential area following joint infusion, both at rest (P = 0.01) and during voluntary muscle contraction (P = 0.02). Cortical silent period duration was significantly reduced following joint infusion (P = 0.02). There were no changes in short interval intracortical inhibition or intracortical facilitation over time (all P > 0.05).

Conclusions

The results of this study provide no evidence for a supraspinal contribution to quadriceps AMI. Paradoxically, but consistent with previous observations in patients with chronic knee joint pathology, quadriceps corticomotor excitability increased after experimental knee joint effusion. The increase in quadriceps corticomotor excitability may be at least partly mediated by a decrease in gamma-aminobutyric acid (GABA)-ergic inhibition within the motor cortex.     

Efficacy of Muscle Exercise in Patients with Muscular Dystrophy: A Systematic Review Showing a Missed Opportunity to Improve Outcomes

Background

Although muscular dystrophy causes muscle weakness and muscle loss, the role of exercise in the management of this disease remains controversial.

Objective

The purpose of this systematic review is to evaluate the role of exercise interventions on muscle strength in patients with muscular dystrophy.

Methods

We performed systematic electronic searches in Medline, Embase, Web of Science, Scopus and Pedro as well as a list of reference literature. We included trials assessing muscle exercise in patients with muscular dystrophy. Two reviewers independently abstracted data and appraised risk of bias.

Results

We identified five small (two controlled and three randomized clinical) trials comprising 242 patients and two ongoing randomized controlled trials. We were able to perform two meta-analyses. We found an absence of evidence for a difference in muscle strength (MD 4.18, 95% CIs - 2.03 to 10.39; p = 0.91) and in endurance (MD −0.53, 95% CIs –1.11 to 0.05; p = 0.26). In both, the direction of effects favored muscle exercise.

Conclusions

The first included trial about the efficacy of muscular exercise was published in 1978. Even though some benefits of muscle exercise were consistently reported across studies, the benefits might be due to the small size of studies and other biases. Detrimental effects are still possible. After several decades of research, doctors cannot give advice and patients are, thus, denied basic information. A multi-center randomized trial investigating the strength of muscles, fatigue, and functional limitations is needed.