scholarly journals Reduced TrkB expression results in precocious age-like changes in neuromuscular structure, neurotransmission, and muscle function

2011 ◽  
Vol 111 (3) ◽  
pp. 844-852 ◽  
Author(s):  
Scott A. Kulakowski ◽  
Sara D. Parker ◽  
Kirkwood E. Personius
Keyword(s):  
Muscle Function ◽  
Acetylcholine Receptors ◽  
Synaptic Function ◽  
Tyrosine Kinase Receptor ◽  
Cross Sectional ◽  
Adult Mice ◽  
Fiber Size ◽  
Muscle Contractile ◽  
Synaptic Stabilization

Acute blockade of signaling through the tyrosine kinase receptor B (TrkB) attenuates neuromuscular transmission and fragments postsynaptic acetylcholine receptors (AChRs) in adult mice, suggesting that TrkB signaling is a key regulator of neuromuscular function. Using immunohistochemical, histological, and in vitro muscle contractile techniques, we tested the hypothesis that constitutively reduced TrkB expression would disrupt neuromuscular pre- and postsynaptic structure, neurotransmission, muscle fiber size, and muscle function in the soleus muscle of 6- to 8-mo-old TrkB+/− mice compared with age-matched littermates. Age-like expansion of postsynaptic AChR area, AChR fragmentation, and denervation was observed in TrkB+/− mice similar to that found in 24-mo-old wild-type mice. Neurotransmission failure was increased in TrkB+/− mice, suggesting that these morphologic changes were sufficient to alter synaptic function. Reduced TrkB expression resulted in decreased muscle strength and fiber cross-sectional area. Immunohistochemical and muscle retrograde labeling experiments show that motor neuron number and size are unaffected in TrkB+/− mice. These results suggest that TrkB- signaling at the neuromuscular junction plays a role in synaptic stabilization, neurotransmission, and muscle function and may impact the aging process of sarcopenia.

scholarly journals Identification of Neuronal Pentraxins as Synaptic Binding Partners of C1q and the Involvement of NP1 in Synaptic Pruning in Adult Mice

2021 ◽  
Vol 11 ◽  
Author(s):  
Réka Á. Kovács ◽  
Henrietta Vadászi ◽  
Éva Bulyáki ◽  
György Török ◽  
Vilmos Tóth ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Synapse Formation ◽  
Potential Interaction ◽  
Synaptic Function ◽  
Classical Pathway ◽  
Microglial Phagocytosis ◽  
Classical Complement Pathway ◽  
Adult Mice ◽  
Synaptic Pruning

Elements of the immune system particularly that of innate immunity, play important roles beyond their traditional tasks in host defense, including manifold roles in the nervous system. Complement-mediated synaptic pruning is essential in the developing and healthy functioning brain and becomes aberrant in neurodegenerative disorders. C1q, component of the classical complement pathway, plays a central role in tagging synapses for elimination; however, the underlying molecular mechanisms and interaction partners are mostly unknown. Neuronal pentraxins (NPs) are involved in synapse formation and plasticity, moreover, NP1 contributes to cell death and neurodegeneration under adverse conditions. Here, we investigated the potential interaction between C1q and NPs, and its role in microglial phagocytosis of synapses in adult mice. We verified in vitro that NPs interact with C1q, as well as activate the complement system. Flow cytometry, immunostaining and co-immunoprecipitation showed that synapse-bound C1q colocalizes and interacts with NPs. High-resolution confocal microscopy revealed that microglia-surrounded C1q-tagged synapses are NP1 positive. We have also observed the synaptic occurrence of C4 suggesting that activation of the classical pathway cannot be ruled out in synaptic plasticity in healthy adult animals. In summary, our results indicate that NPs play a regulatory role in the synaptic function of C1q. Whether this role can be intensified upon pathological conditions, such as in Alzheimer’s disease, is to be disclosed.

scholarly journals Role of TRPC1 channel in skeletal muscle function

2010 ◽  
Vol 298 (1) ◽  
pp. C149-C162 ◽  
Author(s):  
Nadège Zanou ◽  
Georges Shapovalov ◽  
Magali Louis ◽  
Nicolas Tajeddine ◽  
Chiara Gallo ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Function ◽  
Transient Receptor Potential ◽  
Force Production ◽  
Receptor Potential ◽  
Cross Sectional Area ◽  
Sectional Area ◽  
Skeletal Muscle Function ◽  
Cross Sectional

Skeletal muscle contraction is reputed not to depend on extracellular Ca2+. Indeed, stricto sensu , excitation-contraction coupling does not necessitate entry of Ca2+. However, we previously observed that, during sustained activity (repeated contractions), entry of Ca2+is needed to maintain force production. In the present study, we evaluated the possible involvement of the canonical transient receptor potential (TRPC)1 ion channel in this entry of Ca2+and investigated its possible role in muscle function. Patch-clamp experiments reveal the presence of a small-conductance channel (13 pS) that is completely lost in adult fibers from TRPC1−/−mice. The influx of Ca2+through TRPC1 channels represents a minor part of the entry of Ca2+into muscle fibers at rest, and the activity of the channel is not store dependent. The lack of TRPC1 does not affect intracellular Ca2+concentration ([Ca2+]i) transients reached during a single isometric contraction. However, the involvement of TRPC1-related Ca2+entry is clearly emphasized in muscle fatigue. Indeed, muscles from TRPC1−/−mice stimulated repeatedly progressively display lower [Ca2+]itransients than those observed in TRPC1+/+fibers, and they also present an accentuated progressive loss of force. Interestingly, muscles from TRPC1−/−mice display a smaller fiber cross-sectional area, generate less force per cross-sectional area, and contain less myofibrillar proteins than their controls. They do not present other signs of myopathy. In agreement with in vitro experiments, TRPC1−/−mice present an important decrease of endurance of physical activity. We conclude that TRPC1 ion channels modulate the entry of Ca2+during repeated contractions and help muscles to maintain their force during sustained repeated contractions.

scholarly journals The Influence of Supplemental Dietary Linoleic Acid on Skeletal Muscle Contractile Function in a Rodent Model of Barth Syndrome

2021 ◽  
Vol 12 ◽  
Author(s):  
Mario Elkes ◽  
Martin Andonovski ◽  
Daislyn Vidal ◽  
Madison Farago ◽  
Ryan Modafferi ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Linoleic Acid ◽  
Muscle Function ◽  
Barth Syndrome ◽  
Dietary Linoleic Acid ◽  
Skeletal Muscle Function ◽  
Contractile Phenotype ◽  
Muscle Contractile

Barth syndrome is a rare and incurable X-linked (male-specific) genetic disease that affects the protein tafazzin (Taz). Taz is an important enzyme responsible for synthesizing biologically relevant cardiolipin (for heart and skeletal muscle, cardiolipin rich in linoleic acid), a critical phospholipid of mitochondrial form and function. Mutations to Taz cause dysfunctional mitochondria, resulting in exercise intolerance due to skeletal muscle weakness. To date, there has been limited research on improving skeletal muscle function, with interventions focused on endurance and resistance exercise. Previous cell culture research has shown therapeutic potential for the addition of exogenous linoleic acid in improving Taz-deficient mitochondrial function but has not been examined in vivo. The purpose of this study was to examine the influence of supplemental dietary linoleic acid on skeletal muscle function in a rodent model of Barth syndrome, the inducible Taz knockdown (TazKD) mouse. One of the main findings was that TazKD soleus demonstrated an impaired contractile phenotype (slower force development and rates of relaxation) in vitro compared to their WT littermates. Interestingly, this impaired contractile phenotype seen in vitro did not translate to altered muscle function in vivo at the whole-body level. Also, supplemental linoleic acid attenuated, to some degree, in vitro impaired contractile phenotype in TazKD soleus, and these findings appear to be partially mediated by improvements in cardiolipin content and resulting mitochondrial supercomplex formation. Future research will further examine alternative mechanisms of dietary supplemental LA on improving skeletal muscle contractile dysfunction in TazKD mice.

scholarly journals Pubertal induction in adolescents with DMD is associated with high satisfaction, gonadotropin release and increased muscle contractile surface area

2021 ◽  
Vol 184 (1) ◽  
pp. 67-79
Author(s):  
Claire L Wood ◽  
Kieren G Hollingsworth ◽  
Eric Hughes ◽  
Sadhanandham Punniyakodi ◽  
Robert Muni-Lofra ◽  
...  
Keyword(s):  
Muscle Function ◽  
Positive Impact ◽  
Relaxation Times ◽  
Disease Process ◽  
Delayed Puberty ◽  
Muscle Pathology ◽  
Limb Muscle ◽  
Z Score ◽  
Cross Sectional ◽  
Muscle Contractile

Background Pharmacological doses of glucocorticoids (GC) reduce inflammation and preserve muscle function in boys with Duchenne muscular dystrophy (DMD). Delayed puberty and bone fragility are consequences of GC treatment. The aim of this study was to determine the acceptability of a 2-year pubertal induction regimen using 4-weekly testosterone injections and examine changes in physique, bone integrity, muscle pathology (assessed by MRI) and muscle function. Methods Fifteen prepubertal males with DMD, aged 12–17 years and receiving GC, were treated with an incremental testosterone regimen for 2 years. Participants completed a Treatment Satisfaction Questionnaire (TSQM). Data on BMI, bone density, muscle pathology and function were collected at baseline and 2 years later. Results Testosterone injections were well tolerated, with high TSQM scores. Baseline BMI z-score was 2.16 (0.90) and 1.64 (1.35) 2 years later. Median testosterone levels were 9.7 nmol/L (IQR: 5.7–11.1) 6–9 months after the last injection with an associated increase in testicular volume. Lumbar spine z-score was 0.22 (s.d. 2.21) at baseline and 0.35 (s.d. 2.21) after 2 years. Upper and lower limb muscle contractile cross-sectional area increased in all participants during the trial (P = 0.05 and P < 0.01, respectively). There was a reduction in T2 relaxation times in most muscle groups with stable upper limb muscle function. Conclusion Incremental monthly testosterone injections were well tolerated, promoted endogenous testosterone production and had a positive impact on the skeleton and contractile muscle bulk with evidence suggesting a beneficial impact on the underlying disease process.

scholarly journals Myosoft: an automated muscle histology analysis tool using machine learning algorithm utilizing FIJI/ImageJ software

2019 ◽  
Author(s):  
Lucas Encarnacion-Rivera ◽  
Steven Foltz ◽  
H. Criss Hartzell ◽  
Hyo-Jung Choo
Keyword(s):  
Muscle Function ◽  
Learning Algorithm ◽  
Fiber Type ◽  
Muscle Physiology ◽  
Analysis Tool ◽  
Fiber Types ◽  
Accurate Analysis ◽  
Cross Sectional ◽  
Muscle Histology ◽  
Fiber Size

AbstractBackgroundSkeletal muscle is comprised of a heterogeneous population of muscle fibers which can be classified by their metabolic and contractile properties (fiber “types”). Fiber type is a primary determinant of muscle function along with fiber size (cross-sectional area). The fiber type composition of a muscle responds to physiological changes like exercise and aging and is often altered in disease states. Thus, analysis of fiber size and type in histological muscle preparations is a useful method for quantifying key indicators of muscle function and for measuring responses to a variety of stimuli or stressors. These analyses are near-ubiquitous in the fields of muscle physiology and myopathy, but are most commonly performed manually, which is highly labor- and time-intensive. To offset this obstacle, we developed Myosoft, a novel method to automate morphometric and fiber type analysis in muscle sections stained with fluorescent antibodies.MethodsMuscle sections were stained for cell membrane (laminin) and myofiber type (myosin heavy chain isoforms). Myosoft, running in the open access software platform FIJI (ImageJ), was used to analyze myofiber size and type in transverse sections of entire gastrocnemius/soleus muscles.ResultsMyosoft provides accurate analysis of muscle histology >50-times faster than manual analysis. We demonstrate that Myosoft is capable of handling high-content images even when image or staining quality is suboptimal, which is a marked improvement over currently available, comparable programs.ConclusionsMyosoft is a reliable, accurate, high-throughput, and convenient tool to analyze high-content muscle histology. Myosoft is freely available to download from Github at https://github.com/Hyojung-Choo/Myosoft/tree/Myosoft-hub.

scholarly journals Skeletal muscle MACF1 maintains myonuclei and mitochondria localization through microtubules to control muscle functionalities

2019 ◽  
Author(s):  
Alireza Ghasemizadeh ◽  
Emilie Christin ◽  
Alexandre Guiraud ◽  
Nathalie Couturier ◽  
Valérie Risson ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Acetylcholine Receptors ◽  
Neuromuscular Junctions ◽  
Muscular Diseases ◽  
Microtubule Network ◽  
Adult Mice ◽  
Molecular Machinery ◽  
Muscle Excitability

AbstractSkeletal muscle is made from multinuclear myofiber, where myonuclei are positioned at the periphery or clustered below neuromuscular junctions (NMJs). While mispositioned myonuclei are the hallmark of numerous muscular diseases, the molecular machinery maintaining myonuclei positioning in mature muscle is still unknown. Here, we identified microtubule-associated protein MACF1 as an evolutionary conserved regulator of myonuclei positioning, in vitro and in vivo, controlling the “microtubule code” and stabilizing the microtubule dynamics during myofibers maturation, preferentially at NMJs. Specifically, MACF1 governs myonuclei motion, mitochondria positioning and structure and acetylcholine receptors (AChRs) clustering. Macf1-KO in young and adult mice decreases muscle excitability and causes evolutionary myonuclei positioning alterations in adult mice, paralleled with high mitochondria content and improved resistance to fatigue. We present MACF1 as a primary actor of the maintenance of synaptic myonuclei and AChRs clustering, peripheral myonuclei positioning and mitochondria organization through the control of microtubule network dynamics in muscle fibers.

An in vitro Comparison of Two Replacement Techniques Utilizing Fascia Lata after Cranial Cruciate Ligament Transection in the Dog

1993 ◽  
Vol 06 (02) ◽  
pp. 85-92 ◽  
Author(s):  
G. L. Coetzee
Keyword(s):  
Femoral Condyle ◽  
Cruciate Ligament ◽  
Maximum Load ◽  
Fascia Lata ◽  
Patellar Ligament ◽  
Cross Sectional ◽  
Cranial Cruciate Ligament ◽  
Replacement Technique ◽  
Over The Top

SummaryThe immediate postoperative biomechanical properties of an “underand-over” cranial cruciate ligament (CCL) replacement technique consisting of fascia lata and the lateral onethird of the patellar ligament, were compared with that of a modified intra- and extracapsular “under-and-over-the-top” (UOTT) method. The right CCL in twelve adult dogs was dissected out and replaced with an autograft. The contralateral, intact CCL served as the control. In group A, the graft was secured to the lateral femoral condyle with a spiked washer and screw. In group B the intracapsular graft was secured to the lateral femoro-fabellar ligament, and the remainder to the patellar tendon. Both CCL replacement techniques exhibited a 2.0 ± 0.5 mm anterior drawer immediately after the operation. After skeletonization of the stifles, the length and cross-sectional area of the intact CCL and CCL substitutes were determined. Each bone-ligament unit was tested in linear tension to failure at a fixed distraction rate of 15 mm/s with the stifle in 120° flexion. Data was processed to obtain the corresponding material parameters (modulus, stress and strain in the linear loading region, and energy absorption to maximum load).The immediate postoperative structural and material properties of the “under-and-over” cranial cruciate ligament replacement technique with autogenous fascia lata, were compared to that of a modified intra- and extracapsular “under-and-over-the-top” (UOTT) method. The combined UOT T technique was slightly stronger (6%), but allowed 2.8 ± 0.9 mm more cranial tibial displacement at maximum linear force.

Molecular iodine synergized and sensitized neuroblastoma cells to the antineoplastic effect of ATRA

2020 ◽  
Vol 27 (12) ◽  
pp. 699-710
Author(s):  
Irasema Mendieta ◽  
Gabriel Rodríguez-Gómez ◽  
Bertha Rueda-Zarazúa ◽  
Julia Rodríguez-Castelán ◽  
Winniberg Álvarez-León ◽  
...  
Keyword(s):  
Residual Disease ◽  
Neuroblastoma Cells ◽  
Survivin Expression ◽  
Body Weight Loss ◽  
Immunohistochemical Analysis ◽  
Molecular Iodine ◽  
Tyrosine Kinase Receptor ◽  
Adjuvant Effect

Neuroblastoma (NB) is the most common solid childhood tumor, and all-trans retinoic acid (ATRA) is used as a treatment to decrease minimal residual disease. Molecular iodine (I2) induces differentiation and/or apoptosis in several neoplastic cells through activation of PPARγ nuclear receptors. Here, we analyzed whether the coadministration of I2 and ATRA increases the efficacy of NB treatment. ATRA-sensitive (SH-SY5Y), partially-sensitive (SK-N-BE(2)), and non-sensitive (SK-N-AS) NB cells were used to analyze the effect of I2 and ATRA in vitro and in xenografts (Foxn1 nu/nu mice), exploring actions on cellular viability, differentiation, and molecular responses. In the SH-SY5Y cells, 200 μM I2 caused a 100-fold (0.01 µM) reduction in the antiproliferative dose of ATRA and promoted neurite extension and neural marker expression (tyrosine hydroxylase (TH) and tyrosine kinase receptor alpha (Trk-A)). In SK-N-AS, the I2 supplement sensitized these cells to 0.1 μM ATRA, increasing the ATRA-receptor (RARα) and PPARγ expression, and decreasing the Survivin expression. The I2 supplement increased the mitochondrial membrane potential in SK-N-AS suggesting the participation of mitochondrial-mediated mechanisms involved in the sensibilization to ATRA. In vivo, oral I2 supplementation (0.025%) synergized the antitumor effect of ATRA (1.5 mg/kg BW) and prevented side effects (body weight loss and diarrhea episodes). The immunohistochemical analysis showed that I2 supplementation decreased the intratumoral vasculature (CD34). We suggest that the I2 + ATRA combination should be studied in preclinical and clinical trials to evaluate its potential adjuvant effect in addition to conventional treatments.

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