Human motor compensations for thixotropy‐dependent changes in resting wrist joint position after large joint movements

Aim: Resting tension of relaxed skeletal muscle fibres held at a given length varies with the immediate previous history of length changes and contractions. The primary aim of this study was to explore the motor control consequences of this history‐dependency in healthy subjects. Methods: Angular position and passive torque were recorded from the intact wrist joint. Integrated surface electromyography (IEMG) was recorded from wrist extensor and flexor muscles. Results: In relaxed subjects, wrist joint position was displaced towards dorsiflexion after a single high‐amplitude dorsiflexion movement combined with a strong flexor/extensor co‐contraction (dorsiflexion conditioning), whereas after volarflexion conditioning there was a shift towards volarflexion. These after‐effects could be abruptly cancelled by short periods (～5 s) of rapid flapping hand movements or forceful isometric co‐contractions, findings indicative of muscle thixotropy. The IEMG‐evaluated motor after‐effects were as follows. A slowly subsiding wrist flexor contraction was needed to restore and maintain the original resting wrist position after dorsiflexion conditioning whereas a slowly subsiding extensor contraction was needed for the same goal after volarflexion conditioning. Furthermore, ongoing wrist extensor IEMG activity required to actively hold the wrist in a moderate dorsiflexed position or to resist a constant volar torque at resting position was temporarily reduced after dorsiflexion conditioning and enhanced (not significantly) after volarflexion conditioning. Conclusion: The results provide evidence that during voluntary maintenance of a desired wrist joint position the motor commands to the position‐holding muscles are unconsciously adjusted to compensate for thixotropy‐dependent variations in the resting tension of the muscles.     

Human motor compensations for thixotropy-dependent changes in muscular resting tension after moderate joint movements

AIM: This study on healthy subjects explores history-dependent changes in the resting tension of relaxed wrist muscles after moderate joint excursions and the motor control consequences of these changes during voluntary wrist joint position maintenance. METHODS: Integrated surface electromyogram (IEMG) was recorded from wrist extensor/flexor muscles. Angular position and torque were recorded from the wrist joint. Changes in wrist flexor muscle resting tension were sensed by a force transducer pressed against the tendons. RESULTS: Consecutive stepwise changes (7.5 degrees ) in wrist joint position (within the dorsiflexed range) were either imposed on relaxed subjects or actively performed while the subjects under visual guidance tried to mimic the passive movements. In relaxed subjects, passive joint torque resistance at a given steady dorsiflexed position either gradually declined or rose depending on the direction of the previous transition movements. In corresponding voluntary contraction experiments, the IEMG amplitude from position holding wrist extensors was found to vary in a similar way as the passive torque resistance. Further, there was a strong correlation between history-dependent changes in extensor IEMG amplitude and stress alterations exhibited by the relaxed antagonist flexors. The above described, slowly subsiding post-movement mechanical and motor adaptations were accelerated by brief forceful cocontractions of the forearm muscles. CONCLUSION: Moderate stepwise changes in joint position are sufficient to induce history-dependent after-effects in passive muscular resting tension, after-effects which during voluntary position holding are effectively compensated for by the motor control system.     

Human motor compensations for thixotropy-dependent changes in resting wrist joint position after large joint movements

AIM: Resting tension of relaxed skeletal muscle fibres held at a given length varies with the immediate previous history of length changes and contractions. The primary aim of this study was to explore the motor control consequences of this history-dependency in healthy subjects. METHODS: Angular position and passive torque were recorded from the intact wrist joint. Integrated surface electromyography (IEMG) was recorded from wrist extensor and flexor muscles. RESULTS: In relaxed subjects, wrist joint position was displaced towards dorsiflexion after a single high-amplitude dorsiflexion movement combined with a strong flexor/extensor co-contraction (dorsiflexion conditioning), whereas after volarflexion conditioning there was a shift towards volarflexion. These after-effects could be abruptly cancelled by short periods ( approximately 5 s) of rapid flapping hand movements or forceful isometric co-contractions, findings indicative of muscle thixotropy. The IEMG-evaluated motor after-effects were as follows. A slowly subsiding wrist flexor contraction was needed to restore and maintain the original resting wrist position after dorsiflexion conditioning whereas a slowly subsiding extensor contraction was needed for the same goal after volarflexion conditioning. Furthermore, ongoing wrist extensor IEMG activity required to actively hold the wrist in a moderate dorsiflexed position or to resist a constant volar torque at resting position was temporarily reduced after dorsiflexion conditioning and enhanced (not significantly) after volarflexion conditioning. CONCLUSION: The results provide evidence that during voluntary maintenance of a desired wrist joint position the motor commands to the position-holding muscles are unconsciously adjusted to compensate for thixotropy-dependent variations in the resting tension of the muscles.     

PDGFRα signalling promotes fibrogenic responses in collagen‐producing cells in Duchenne muscular dystrophy

Fibrosis is a characteristic of Duchenne muscular dystrophy (DMD), yet the cellular and molecular mechanisms responsible for DMD fibrosis are poorly understood. Utilizing the Collagen1a1‐GFP transgene to identify cells producing Collagen‐I matrix in wild‐type mice exposed to toxic injury or those mutated at the dystrophin gene locus (mdx) as a model of DMD, we studied mechanisms of skeletal muscle injury/repair and fibrosis. PDGFRα is restricted to Sca1+, CD45? mesenchymal progenitors. Fate‐mapping experiments using inducible CreER/LoxP somatic recombination indicate that these progenitors expand in injury or DMD to become PDGFRα+, Col1a1‐GFP+ matrix‐forming fibroblasts, whereas muscle fibres do not become fibroblasts but are an important source of the PDGFRα ligand, PDGF‐AA. While in toxin injury/repair of muscle PDGFRα, signalling is transiently up‐regulated during the regenerative phase in the DMD model and in human DMD it is chronically overactivated. Conditional expression of the constitutively active PDGFRα D842V mutation in Collagen‐I+ fibroblasts, during injury/repair, hindered the repair phase and instead promoted fibrosis. In DMD, treatment of mdx mice with crenolanib, a highly selective PDGFRα/β tyrosine kinase inhibitor, reduced fibrosis, improved muscle strength, and was associated with decreased activity of Src, a downstream effector of PDGFRα signalling. These observations are consistent with a model in which PDGFRα activation of mesenchymal progenitors normally regulates repair of the injured muscle, but in DMD persistent and excessive activation of this pathway directly drives fibrosis and hinders repair. The PDGFRα pathway is a potential new target for treatment of progressive DMD. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

X‐linked spinal muscular atrophy in mice caused by autonomous loss of ATP7A in the motor neuron

ATP7A is a copper‐transporting P‐type ATPase that is essential for cellular copper homeostasis. Loss‐of‐function mutations in the ATP7A gene result in Menkes disease, a fatal neurodegenerative disorder resulting in seizures, hypotonia and failure to thrive, due to systemic copper deficiency. Most recently, rare missense mutations in ATP7A that do not impact systemic copper homeostasis have been shown to cause X‐linked spinal muscular atrophy type 3 (SMAX3), a distal hereditary motor neuropathy. An understanding of the mechanistic and pathophysiological basis of SMAX3 is currently lacking, in part because the disease‐causing mutations have been shown to confer both loss‐ and gain‐of‐function properties to ATP7A, and because there is currently no animal model of the disease. In this study, the Atp7a gene was specifically deleted in the motor neurons of mice, resulting in a degenerative phenotype consistent with the clinical features in affected patients with SMAX3, including the progressive deterioration of gait, age‐dependent muscle atrophy, denervation of neuromuscular junctions and a loss of motor neuron cell bodies. Taken together, these data reveal autonomous requirements for ATP7A that reveal essential roles for copper in the maintenance and function of the motor neuron, and suggest that SMAX3 is caused by a loss of ATP7A function that specifically impacts the spinal motor neuron. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Structural Implications of β‐Cardiac Myosin Heavy Chain Mutations in Human Disease

Over 500 disease‐causing point mutations have been found in the human β‐cardiac myosin heavy chain, many quite recently with modern sequencing techniques. This review shows that clusters of these mutations occur at critical points in the sequence and investigates whether the many studies on these mutants reveal information about the function of this protein. Anat Rec, 297:1670–1680, 2014. © 2014 Wiley Periodicals, Inc.     

Time‐dependent diffusion MRI as a probe of microstructural changes in a mouse model of Duchenne muscular dystrophy

Dystrophic muscles show a high variability of fibre sizes and altered sarcolemmal integrity, which are typically assessed by histology. Time‐dependent diffusion MRI is sensitive to tissue microstructure and its investigation through age‐related changes in dystrophic and healthy muscles may help the understanding of the onset and progression of Duchenne muscular dystrophy (DMD). We investigated the capability of time‐dependent diffusion MRI to quantify age and disease‐related changes in hind‐limb muscle microstructure between dystrophic (mdx) and wild‐type (WT) mice of three age groups (7.5, 22 and 44 weeks). Diffusion time‐dependent apparent diffusion coefficients (ADCs) of the gastrocnemius and tibialis anterior muscles were determined versus age and diffusion‐gradient orientation at six diffusion times (Δ; range: 25–350 ms). Mean muscle ADCs were compared between groups and ages, and correlated with T₂, using Student's t test, one‐way analysis of variance and Pearson correlation, respectively. Muscle fibre sizes and sarcolemmal integrity were evaluated by histology and compared with diffusion measurements. Hind‐limb muscle ADC showed characteristic restricted diffusion behaviour in both mdx and WT animals with decreasing ADC values at longer Δ. Significant differences in ADC were observed at long Δ values (≥ 250 ms; p < 0.05, comparison between groups; p < 0.01, comparison between ages) with ADC increased by 5–15% in dystrophic muscles, indicative of reduced diffusion restriction. No significant correlation was found between T₂ and ADC. Additionally, muscle fibre size distributions showed higher variability and lower mean fibre size in mdx than WT animals (p < 0.001). The extensive Evans Blue Dye uptake shown in dystrophic muscles revealed substantial sarcolemmal damage, suggesting diffusion measurements as more consistent with altered permeability rather than changes in muscle fibre sizes. This study shows the potential of diffusion MRI to non‐invasively discriminate between dystrophic and healthy muscles with enhanced sensitivity when using long Δ.     

Novel LMNA mutations in patients with Emery‐Dreifuss muscular dystrophy and functional characterization of four LMNA mutations

Mutations in LMNA cause a variety of diseases affecting striated muscle including autosomal Emery‐Dreifuss muscular dystrophy (EDMD), LMNA‐associated congenital muscular dystrophy (L‐CMD), and limb‐girdle muscular dystrophy type 1B (LGMD1B). Here, we describe novel and recurrent LMNA mutations identified in 50 patients from the United States and Canada, which is the first report of the distribution of LMNA mutations from a large cohort outside Europe. This augments the number of LMNA mutations known to cause EDMD by 16.5%, equating to an increase of 5.9% in the total known LMNA mutations. Eight patients presented with either p.R249W/Q or p.E358K mutations and an early onset EDMD phenotype: two mutations recently associated with L‐CMD. Importantly, 15 mutations are novel and include eight missense mutations (p.R189P, p.F206L, p.S268P, p.S295P, p.E361K, p.G449D, p.L454P, and p.W467R), three splice site mutations (c.IVS4 + 1G>A, c.IVS6 ? 2A>G, and c.IVS8 + 1G>A), one duplication/in frame insertion (p.R190dup), one deletion (p.Q355del), and two silent mutations (p.R119R and p.K270K). Analysis of 4 of our lamin A mutations showed that some caused nuclear deformations and lamin B redistribution in a mutation specific manner. Together, this study significantly augments the number of EDMD patients on the database and describes 15 novel mutations that underlie EDMD, which will contribute to establishing genotype–phenotype correlations. Hum Mutat 31:–16, 2011. © 2011 Wiley‐Liss, Inc.     

GARS‐related disease in infantile spinal muscular atrophy: Implications for diagnosis and treatment

The majority of patients with spinal muscular atrophy (SMA) identified to date harbor a biallelic exonic deletion of SMN1. However, there have been reports of SMA‐like disorders that are independent of SMN1, including those due to pathogenic variants in the glycyl‐tRNA synthetase gene (GARS1). We report three unrelated patients with de novo variants in GARS1 that are associated with infantile‐onset SMA (iSMA). Patients were ascertained during inpatient hospital evaluations for complications of neuropathy. Evaluations were completed as indicated for clinical care and management and informed consent for publication was obtained. One newly identified, disease‐associated GARS1 variant, identified in two out of three patients, was analyzed by functional studies in yeast complementation assays. Genomic analyses by exome and/or gene panel and SMN1 copy number analysis of three patients identified two previously undescribed de novo missense variants in GARS1 and excluded SMN1 as the causative gene. Functional studies in yeast revealed that one of the de novo GARS1 variants results in a loss‐of‐function effect, consistent with other pathogenic GARS1 alleles. In sum, the patients' clinical presentation, assessments of previously identified GARS1 variants and functional assays in yeast suggest that the GARS1 variants described here cause iSMA. GARS1 variants have been previously associated with Charcot–Marie–Tooth disease (CMT2D) and distal SMA type V (dSMAV). Our findings expand the allelic heterogeneity of GARS‐associated disease and support that severe early‐onset SMA can be caused by variants in this gene. Distinguishing the SMA phenotype caused by SMN1 variants from that due to pathogenic variants in other genes such as GARS1 significantly alters approaches to treatment.     

T2 mapping provides multiple approaches for the characterization of muscle involvement in neuromuscular diseases: a cross‐sectional study of lower leg muscles in 5–15‐year‐old boys with Duchenne muscular dystrophy

Skeletal muscles of children with Duchenne muscular dystrophy (DMD) show enhanced susceptibility to damage and progressive lipid infiltration, which contribute to an increase in the MR proton transverse relaxation time (T₂). Therefore, the examination of T₂ changes in individual muscles may be useful for the monitoring of disease progression in DMD. In this study, we used the mean T₂, percentage of elevated pixels and T₂ heterogeneity to assess changes in the composition of dystrophic muscles. In addition, we used fat saturation to distinguish T₂ changes caused by edema and inflammation from fat infiltration in muscles. Thirty subjects with DMD and 15 age‐matched controls underwent T₂‐weighted imaging of their lower leg using a 3‐T MR system. T₂ maps were developed and four lower leg muscles were manually traced (soleus, medial gastrocnemius, peroneal and tibialis anterior). The mean T₂ of the traced regions of interest, width of the T₂ histograms and percentage of elevated pixels were calculated. We found that, even in young children with DMD, lower leg muscles showed elevated mean T₂, were more heterogeneous and had a greater percentage of elevated pixels than in controls. T₂ measures decreased with fat saturation, but were still higher (P < 0.05) in dystrophic muscles than in controls. Further, T₂ measures showed positive correlations with timed functional tests (r = 0.23–0.79). The elevated T₂ measures with and without fat saturation at all ages of DMD examined (5–15 years) compared with unaffected controls indicate that the dystrophic muscles have increased regions of damage, edema and fat infiltration. This study shows that T₂ mapping provides multiple approaches that can be used effectively to characterize muscle tissue in children with DMD, even in the early stages of the disease. Therefore, T₂ mapping may prove to be clinically useful in the monitoring of muscle changes caused by the disease process or by therapeutic interventions in DMD. Copyright © 2012 John Wiley & Sons, Ltd.     

Time‐dependent diffusion in skeletal muscle with the random permeable barrier model (RPBM): application to normal controls and chronic exertional compartment syndrome patients

The purpose of this work was to carry out diffusion tensor imaging (DTI) at multiple diffusion times T_d in skeletal muscle in normal subjects and chronic exertional compartment syndrome (CECS) patients and analyze the data with the random permeable barrier model (RPBM) for biophysical specificity. Using an institutional review board approved HIPAA‐compliant protocol, seven patients with clinical suspicion of CECS and eight healthy volunteers underwent DTI of the calf muscle in a Siemens MAGNETOM Verio 3 T scanner at rest and after treadmill exertion at four different T_d values. Radial diffusion values λ_rad were computed for each of seven different muscle compartments and analyzed with RPBM to produce estimates of free diffusivity D₀, fiber diameter a, and permeability κ. Fiber diameter estimates were compared with measurements from literature autopsy reference for several compartments. Response factors (post/pre‐exercise ratios) were computed and compared between normal controls and CECS patients using a mixed‐model two‐way analysis of variance. All subjects and muscle compartments showed nearly time‐independent diffusion along and strongly time‐dependent diffusion transverse to the muscle fibers. RPBM estimates of fiber diameter correlated well with corresponding autopsy reference. D₀ showed significant (p < 0.05) increases with exercise for volunteers, and a increased significantly (p < 0.05) in volunteers. At the group level, response factors of all three parameters showed trends differentiating controls from CECS patients, with patients showing smaller diameter changes (p = 0.07), and larger permeability increases (p = 0.07) than controls. Time‐dependent diffusion measurements combined with appropriate tissue modeling can provide enhanced microstructural specificity for in vivo tissue characterization. In CECS patients, our results suggest that high‐pressure interfiber edema elevates free diffusion and restricts exercise‐induced fiber dilation. Such specificity may be useful in differentiating CECS from other disorders or in predicting its response to either physical therapy or fasciotomy. Copyright © 2014 John Wiley & Sons, Ltd.     

ENU‐3 functions in an UNC‐6/netrin dependent pathway parallel to UNC‐40/DCC/frazzled for outgrowth and guidance of the touch receptor neurons in C. elegans

Results: An enu‐3 mutation enhances defects in ventral guidance of the processes of the AVM and PVM touch receptor neurons, the dorsal guidance of the distal tip cell and causes additional architectural defects in axons in unc‐40 mutant strains in an UNC‐6 dependent manner. These observations suggest that ENU‐3 and UNC‐40 function in parallel pathways dependent on UNC‐6. ENU‐3 depends on the presence of UNC‐40 for its full effect on motor neuron axon outgrowth. 相似文献   

Relationships between muscle morphology and insulin sensitivity are improved after adjustment for intra‐individual variability in 70‐year‐old men

The purpose of this investigation was to examine to what extent variability in the muscle morphology and insulin sensitivity influence the correlation between them. Reproducibility of muscle characteristics was estimated in duplicate biopsies from the same thigh of 23 subjects from a cohort of 70‐year‐old men. The coefficient of variation (CV) for different characteristics of muscle morphology was between 11 and 42% in duplicate biopsies. Coefficient of variation for markers of insulin sensitivity ranged between 12 and 39%. The variability reflected by intra‐class correlation ranged from 0.23 to 0.60 for muscle morphology and from 0.68 to 0.96 for estimates of insulin sensitivity. The correlation analysis between muscle morphology and insulin resistance was performed in a sample of 515 men from the cohort, correlation coefficients were calculated with (r_true) and without (r) adjustment for intra‐individual variation. Insulin sensitivity showed a positive relationship with percentage of type I fibres (r_true=0.33, r=0.21; P < 0.0001) and capillary density (r_true=0.43, r=0.21; P < 0.0001) and negative correlations with percentage of type IIB fibres (r_true=–0.35, r=–0.24; P < 0.0001). Capillary density was inversely correlated to insulin. Thus, an obvious improvement of the correlation was seen after correcting intra‐individual variation. In conclusion, owing to the low degree of reproducibility of muscle morphology variables and insulin sensitivity, implying a noticeable underestimation of correlations, the r‐values should be adjusted for within‐subject variation in order to demonstrate a more accurate estimate of the strength of the relationships studied.