We tested the hypothesis that eccentric contractions (ECCs) rapidly induce greater-than-normal isometric torque drop in dystrophin-deficient golden retriever muscular dystrophy (GRMD) muscles. ECCs were imposed by forcibly stretching activated muscles. The results indicate that isometric torque drop was greater in GRMD versus controls (P < 0.0001). Our findings support the hypothesis that ECCs induce greater-than-normal isometric torque drop in GRMD muscles. The magnitude of ECC-induced isometric torque loss may be an ideal clinical endpoint in the GRMD model.
Duchenne muscular dystrophy; golden retriever muscular dystrophy; stretch; dystrophin; muscle damage
Both grip and knee extension strength are often used to characterize overall limb muscle strength. We sought to determine if the measures actually reflect a common construct.
The isometric grip and knee extension strength of 164 healthy men and women (18–85 years) were measured bilaterally using standard procedures. Pearson correlations (r), Cronbach alpha, principal components analysis and multiple regression/correlation were used to investigate the dimensionality of the measures.
Left and right grip forces and knee extension torques were highly correlated, internally consistent, and loaded on a single component. Gender and age explained the variance in both measures, but height added to the explanation of grip strength, whereas weight added to the explanation of knee extension strength.
Among healthy adults, grip and knee extension strength reflect a common underlying construct. The measures, however, are affected differently by height and weight.
Muscle; strength; measurement; grip; knee
We established a colony of dogs that harbor an X-linked MTM1 missense mutation. Muscle from affected male dogs exhibits reduction and altered localization of the MTM1 gene product, myotubularin, and provides a model analogous to X-linked myotubular myopathy (XLMTM).
We studied hind limb muscle function in age-matched canine XLMTM genotypes between ages 9 and 18 weeks.
By the end of the study, affected dogs produce only ~15% of the torque generated by normals or carriers (0.023 ± 0.005 vs 0.152 ± 0.007 and 0.154 ± 0.003 N-m/Kg body mass, respectively, p <0.05) and are too weak to stand unassisted. At this age, XLMTM dogs also demonstrate an abnormally low twitch:tetanus ratio, a right-shifted torque-frequency relationship and an increase in torque during repetitive stimulation (p<0.05).
We hypothesize that muscle weakness results from impaired excitation-contraction (E-C) coupling. Interventions that improve E-C coupling might be translated from the XLMTM dog model to patients.
myotubular myopathy; stretch; myotubularin; muscle damage; strength; function
Non-dystrophic Myotonia (NDM) is characterized by myotonia without muscle wasting. A standardized quantitative myotonia assessment (QMA) is important for clinical trials.
Myotonia was assessed in 91 individuals enrolled in a natural history study using a commercially available computerized handgrip myometer and automated software. Average peak force and 90% to 5% relaxation times were compared to historical normal controls studied with identical methods.
30 subjects had chloride channel mutations, 31 sodium channel mutations, 6 DM2, and 24 no identified mutation. Chloride channel mutations were associated with prolonged 1st handgrip relaxation times, and warm up on subsequent handgrips. Sodium channel mutations were associated with prolonged 1st handgrip relaxation times and paradoxical myotonia or warm-up, depending on underlying mutations. DM2 subjects had normal relaxation times but decreased peak force. Sample size estimates are provided for clinical trial planning.
QMA is an automated, non-invasive technique for evaluating myotonia in NDM.
natural history; ion channel mutation; muscle disease; myotonia; non-dystrophic myotonia
We describe a patient with a prolonged myasthenic crisis refractory to conventional immunomodulatory treatments who was treated with GM-CSF (granulocyte macrophage colony stimulating factor, sargramostim).
T regulatory cell (Tregs) suppressive function and Foxp3 expression were evaluated before and after treatment with GM-CSF.
Treatment with GM-CSF was associated with clinical improvement, an expansion of the circulating numbers of Foxp3+ cells, an increase in Foxp3 expression levels in Tregs, an early improvement in Treg suppressive capacity for AChR-α induced T cell proliferation, and a subsequent enhancement in Treg suppression of polyclonal T cell proliferation.
Although definitive conclusions cannot be drawn from 1 case, the correlation with similar findings in GM-CSF treated animals with experimental autoimmune myasthenia gravis suggests further exploration of the effects of GM-CSF in myasthenia gravis should be studied in a clinical trial setting.
GM-CSF; Myasthenia; regulatory T cells; immunology; Foxp3; sargramostim
Charcot–Marie–Tooth (CMT) disease results in distal lower limb weakness that affects walking. In this study we assess the role of the hip flexors in compensating for distal weakness while walking and the effects of prolonged walking on these putative compensatory strategies. Eighteen subjects with CMT disease were compared with 14 matched controls while they walked on a treadmill to a predetermined point of perceived effort. A significant reduction was observed in peak hip flexor velocity during walking and hip flexor maximal voluntary contraction. In a second session following selective fatigue of the hip flexors, hip flexor velocity decreased immediately on walking, and walking duration was greatly reduced. This study suggests that hip flexors compensate for distal weakness and that fatigue in the hip flexors can limit walking duration. Treatments directed toward improving proximal muscle strength may therefore help to delay onset of hip flexor fatigue and thus prolong walking duration.
Here we review recent research into the mechanisms of chronic pain that has focused on neuronal sodium channels, a target of classic analgesic agents. We first discuss evidence that specific sodium channel isoforms are essential for the detection and conduction of normal acutely painful stimuli from nociceptors. We then review findings that show changes in sodium channel expression and localization in chronic inflammation and nerve injury in animal and human tissues. We conclude by discussing the role that myelination plays in organizing and maintaining sodium channel clusters at nodes of Ranvier in normal development and how inflammatory processes or nerve injury alter the characteristics of such clusters. Based on these findings, we suggest that chronic pain may in part result from partial demyelination of axons during chronic injury, which creates aberrant sodium channel clusters that serve as sites of ectopic sensitivity or spontaneous activity.
sodium channels; chronic pain; nociception; demyelination; nodes of Ranvier
Electrical impedance myography (EIM) is a non-invasive technique used for assessment of muscle health in which a high-frequency, low-amplitude electric current is applied to the skin overlying a muscle, and the resulting surface voltage is measured. We have previously used adhesive electrodes, application of which is inconvenient. We present data using a handheld electrode array (HEA) that we devised to expedite the EIM procedure in a clinical setting.
Thirty-four healthy volunteers and 24 radiculopathy subjects underwent EIM testing using the HEA and adhesive electrodes.
The HEA was shown to have good test-retest reproducibility, with intraclass correlation coefficients as high as 0.99. HEA data correlated strongly with data from adhesive electrodes, ρ = 0.85 in healthy volunteers (p < 0.001) and ρ = 0.75 in radiculopathy subjects (p < 0.001).
These data support the potential use of a handheld array for performing rapid localized surface impedance measurements.
electrical impedance; radiculopathy; subcutaneous fat; muscle; reproducibility
Mutations in the gene that encodes filamin C, FLNC, represent a rare cause of a distinct type of myofibrillar myopathy (MFM).
We investigated an Italian patient by means of muscle biopsy, muscle and brain imaging and molecular analysis of MFM genes.
The patient harbored a novel 7256C>T, p.Thr2419Met mutation in exon 44 of FLNC. Clinical, pathological and muscle MRI findings were similar to the previously described filaminopathy cases. This patient had, in addition, cerebellar ataxia with atrophy of cerebellum and vermis evident on brain MRI scan. Extensive screening failed to establish a cause of cerebellar atrophy.
We report an Italian filaminopathy patient, with a novel mutation in a highly conserved region. This case raises the possibility that the disease spectrum caused by FLNC may include cerebellar dysfunction.
filaminopathy; FLNC; myofibrillar myopathy; cerebellar ataxia; muscle MRI
This investigation aimed to: 1) confirm whether women were more vulnerable to the negative neuromuscular adaptations elicited by muscle unloading and if so, 2) determine which physiological mechanism(s) explain those gender-related differences.
Healthy young men (20.7 ± 0.3 yrs) and women (20.3 ± 0.3 yrs) - (N=12/group) -participated by completing neuromuscular functional tests before and after 7 d of unloading.
During isokinetic testing of peak torque, work performed, and power, women displayed significantly (P ≤ 0.05) greater declines in performance than men at 1.05 and 2.09, but not 0.53 rads/s. During maximal isometric contractions, women experienced greater strength decrements. Similar gender-specific adaptations to unloading were found in EMG activity, but not muscle mass, neuromuscular transmission, or force relative to EMG.
Women are more susceptible to the adaptations of muscle unloading, and disturbances in neural drive from the central nervous system are probably responsible.
atrophy; disuse; gender; unweighting; neuromuscular
Deficits in voluntary force generation may be due to incomplete activation or decreased maximum force generating ability (MFGA) of the targeted muscle. The validity of techniques used to measure MFGA in individuals post-stroke has not been assessed. The objective of this study is to determine the reliability of the MFGA predicted using an adjusted burst superimposition method within a post-stroke population.
Differences in paretic-side plantar flexor muscle MFGA between two trials was calculated using the standard and adjusted burst superimposition technique for 17 individuals post-stroke (15 men, 58.7 ± 10 yrs, 6+ months post-stroke) to assess reliability of the techniques.
The adjusted measurement was shown to be more reliable (p=0.03), especially when volitional effort differed by more than 40 N.
Reliable measurement of the MFGA in individuals who have sustained a stroke is of clinical importance. These results suggest that the adjusted burst superimposition method may be useful when performing multiple measurements of muscle performance.
Maximum force generating ability; Burst superimposition; Plantar flexors; Stroke; Functional Electrical Stimulation
The purpose of this study is to provide a controlled trial looking at the risk of paraspinal hematoma formation following extensive paraspinal muscle electromyography.
54 subjects ages 55-80 underwent MRI of the lumbar spine before or shortly after electromyography using the paraspinal mapping technique. A neuroradiologist, blinded to the temporal relationship between the EMG and MRI, reviewed the MRIs to look for hematomas in or around the paraspinal muscles.
Two MRIs demonstrated definite paraspinal hematomas, while 10 were found to have possible hematomas. All hematomas were < 15 mm, and none were close to any neural structures. There was no relationship between MRI evidence of hematoma and either the timing of the EMG or the use of aspirin or other non-steroidal anti-inflammatory drugs.
Paraspinal electromyography can be considered safe in the general population and those taking non-steroidal anti-inflammatory drugs.
Electromyography; Paraspinal muscles; Hematoma; Paraspinal mapping; Complications
Resistance exercise (RE) stimulates a muscle protein anabolic response partially through enhanced satellite cell (SC) activity, however, age and gender-related changes in SC content over a 24h time course are not known.
Ten young (27±2y) men and women and eleven older (70±2y) men and women performed an acute bout of RE. Myofiber and SC characteristics were determined from muscle biopsies of the vastus lateralis using immunohistochemistry. Immunoblotting was used to determine phosphorylation of cyclin dependent kinase-2 and protein expression of p27Kip1 and cyclin D1.
Pax7+ SC were significantly increased in young men 24h following RE. Percent SC were significantly increased in older women at 6 and 24h following RE. Aging decreased myonuclear domain and increased protein expression of p27Kip1.
An acute bout of RE increases SC content in young men at 24h and older women at 6 and 24h.
aging; cell cycle; muscle; myonuclear domain; gender
The purpose was to examine relations among spasticity, weakness, force variability, and sustained spontaneous motor unit discharges in spastic-paretic biceps brachii muscles in chronic stroke.
Ten chronic stroke subjects produced submaximal isometric elbow flexion force on impaired and non-impaired sides. Intramuscular EMG (iEMG) was recorded from biceps and triceps brachii muscles.
We observed sustained spontaneous motor unit discharges in the resting biceps on iEMG. Spontaneous discharges increased after voluntary activation only on the impaired side. The impaired side had greater matching errors and greater fluctuations in isometric force. Spontaneous discharges were not functionally related to spasticity, force variability, or weakness. However, greater strength on the impaired side correlated with less force variability.
Weakness rather than spasticity is a main factor interfering with voluntary force control in paretic-spastic biceps brachii muscles in chronic stroke.
stroke; electromyography (EMG); force; sustained motor unit spontaneous discharges; variability; spasticity; hemiparesis
Neuromuscular disorders frequently complicate sepsis and other critical illnesses in patients. Mice are the major species used as a model for sepsis. Nerve conduction studies (NCS), the primary tool for noninvasive assessment of nerve and muscle function, is challenging to perform in small animals. A reliable method for noninvasive, repeated NCS testing has not been reported in mice. We developed and validated a method for the repeated measurement of mouse sciatic nerve conduction in normal and septic mice. Our sedated and awake NCS system enabled minimally invasive long-term repeated measurements. The mean compound muscle action potential (CMAP) amplitude and latency were 17.4 mV and 1.11 ms, respectively (n = 59). There was an excellent intertester reproducibility by linear regression in both normal (r = 0.95) and septic (r = 0.98) mice. We also showed significant, time-dependent isoflurane-induced CMAP suppression in all animals, which was further exacerbated in septic mice. This study provides a new tool for the assessment of peripheral nerve/muscle function in mouse neuromuscular disease models that require repeated, long-term, and minimally invasive monitoring.
EMG; sciatic nerve conduction; normative data; reliability; long-term; isoflurane; sepsis; mouse
Muscle weakness can be caused by decreases in either the maximum force generating ability of a muscle (MFGA) or neural drive from the nervous system (e.g., following a stroke). Presently, there is no agreed upon practical method for calculating the MFGA in individuals with central nervous system pathology. The purpose of this study was to identify the best method of determining the MFGA.
The predicted and estimated MFGA of the muscles of 23 non-neurologically impaired subjects (13M, 21.9 +/- 1.9 years) were compared using the burst superimposition, twitch interpolation, doublet interpolation, twitch-to-tetanus ratio, and adjusted burst superimposition methods.
The adjusted burst superimposition test was the most accurate predictor of MFGA.
Further testing is needed to validate the use of the adjusted burst superimposition test in a neurologically impaired population.
Maximum force generating ability; Volitional activation ratio; Burst superimposition; Twitch interpolation; Doublet interpolation
Rapid progress in the discovery of motor neuron disease genes in amyotrophic lateral sclerosis, the spinal muscular atrophies, hereditary motor neuropathies, and lethal congenital contracture syndromes is providing new perspectives and insights into the molecular pathogenesis of the motor neuron. Motor neuron disease genes are often expressed throughout the body with essential functions in all cells. A survey of these functions indicates that motor neurons are uniquely sensitive to perturbations in RNA processing pathways dependent upon the interaction of specific RNAs with specific RNA-binding proteins, which presumably result in aberrant formation and function of ribonucleoprotein complexes. This review provides a summary of currently recognized RNA processing defects linked to human motor neuron diseases.
amyotrophic lateral sclerosis; spinal muscular atrophy; hereditary neuropathy; RNA processing
Increased reliance on bulbospinal motor systems has been implicated in individuals with chronic stroke during maximum voluntary arm joint torque generation.
Maximum isometric single-joint and multi-joint arm strength were observed in two body orientations (sitting & supine) while maintaining identical head/neck/trunk/extremity joint configurations in order to identify bulbospinal contributions to maximum joint torque generation in 11 individuals with stroke and 10 individuals without stroke.
During sitting, shoulder flexion was greater for both groups, while shoulder extension and elbow flexion, part of the “flexion synergy,” were greater only in individuals with stroke.
The results demonstrate that body orientation influences isometric arm strength, notably the constituents of flexion synergy in individuals with stroke, suggesting bulbospinal motor pathway involvement. From a practical perspective, clinical evaluation of single joint strength in the supine position may underestimate strength available during activities of daily living that are performed in an upright orientation.
stroke; body orientation; upper extremity; isometric; torque
Miller Fisher syndrome (MFS), a rare variant of Guillan-Barré syndrome, is characterized by ophthalmoplegia, ataxia, and areflexia. In addition to this classic triad, symptoms may include bulbar palsy, weakness, and sensory loss. The anti-GQ1b IgG antibody is a sensitive and specific marker for MFS; it is found in more than 90% of affected patients. We describe an unusual case of MFS that presented with dramatic bilateral proptosis and chemosis.
Miller Fisher syndrome; Guillain Barré syndrome; proptosis; GQ1b antibody; ophthalmoplegia
This report is a meta-analysis of the human muscle architecture literature that analyzes the number of muscles, number of subjects, and muscle fiber length coefficient of variation (CV) by body region.
Muscle fiber length data are used to make recommendations for dissection-based architectural study sample sizes.
An average of 9 ± 10 (mean ± SD) muscles and an average of 9 ± 5 subjects were reported in the 26 studies considered. Across all studies, average fiber length CV was highly variable (18% ± 5%). This shows that sample sizes required to achieve adequate power varies by anatomical region.
Studies involving muscle architecture should consider regional variability and effect size and determine sample size accordingly.
muscle; architecture; sample size; fiber length variation; statistical power
The correlation between monofilament testing, symptom surveys and electrodiagnostic studies for the diagnosis of axonal polyneuropathy has not been well studied. This study was to assess the agreement between these procedures in a non-random sample of volunteers.
The evaluated procedures included electrodiagnostic tests of the sural nerve, monofilament testing of the great toe, a symptom survey and a body diagram. Kappa coefficients, sensitivity and specificity, using nerve conduction as a ‘gold standard’, were used to determine the agreement between various combinations of procedures.
Poor agreement (Kappa values: −0.12 ~ 0.44) and sensitivity (sensitivity<30%) were found for all combinations of symptoms and monofilament results in comparison with sural peak latency and amplitude.
Overall, the results demonstrated a low discriminatory power for the screening procedures for identifying persons with impaired sural nerve function. The results highlight the need for further development and evaluation of screening methods for distal neuropathy in population-based studies.
Nerve Conduction; Sural Nerve; Monofilament; Symptom; Agreement
Stiff Person Syndrome (SPS) is a disabling autoimmune CNS disorder characterized by progressive muscle rigidity and gait impairment with superimposed painful spasms that involve axial and limb musculature, triggered by heightened sensitivity to external stimuli. Impaired synaptic GABAergic inhibition resulting from intrathecal B-cell-mediated clonal synthesis of autoantibodies against various presynaptic and synaptic proteins in the inhibitory neurons of the brain and spinal cord is believed to be an underlying pathogenic mechanism. SPS is most often idiopathic, but it can occur as a paraneoplastic condition. Despite evidence that anti-GAD and related autoantibodies impair GABA synthesis, the exact pathogenic mechanism of SPS is not fully elucidated. The strong association with several MHC-II alleles and improvement of symptoms with immune-modulating therapies support an autoimmune etiology of SPS. In this review, we discuss the clinical spectrum, neurophysiological mechanisms, and therapeutic options, including a rationale for agents that modulate B cell function in SPS.
GABA; anti-GAD antibodies; stiff person syndrome; autoimmunity; paraneoplastic disorders
The purpose of this study was to compare the capability of interference and rectified electromyography (EMG) to detect changes in the beta (13–30-HZ) and Piper (30–60-HZ) bands when voluntary force is increased. Twenty adults exerted a constant force abduction of the index finger at 15% and 50% of maximum. The common oscillations at various frequency bands (0–500 HZ) were estimated from the first dorsal interosseous muscle using cross wavelets of interference and rectified EMG. For the interference EMG signals, normalized power significantly (P < 0.01) increased with force in the beta (9.0 ± 0.9 vs. 15.5 ± 2.1%) and Piper (13.6 ± 0.9 vs. 21 ± 1.7%) bands. For rectified EMG signals, however, the beta and Piper bands remained unchanged (P > 0.4). Although rectified EMG is used in many clinical studies to identify changes in the oscillatory drive to the muscle, our findings suggest that only interference EMG can accurately capture the increase in oscillatory drive from 13 to 60 HZ with voluntary force.
beta band; cross-wavelet; oscillations; Piper band; rectification
The purpose of this study was to test the hypothesis that Malignant Hyperthermia model mice (RyR1Y522S/wt) are more vulnerable to exercise-induced muscle injury and fatigability and adapt less to run training.
Following 6 weeks of voluntary wheel running, we measured anterior crural muscle fatigability, muscle injury, and cytochrome oxidase (COX) and citrate synthase (CS).
Although RyR1Y522S/wt mice ran without experiencing MH episodes, they ran 42% less distance than wild type (WT) mice. Muscles from WT mice exhibited increased fatigue resistance and COX content after training. Muscles from RyR1Y522S/wt mice demonstrated no significant change in fatigability or COX and CS after training. However, muscles from RyR1Y522S/wt mice displayed less intrinsic fatigability and greater COX/CS content and muscle damage than WT mice.
RyR1Y522S/wt mice can run without experiencing rhabdomyolysis, and their inability to adapt to training appears to stem from intrinsic enhancement of mitochondrial enzymes and fatigue resistance.
ryanodine receptor; injury; adaptation; mitochondria; calcium