Fibroblast-derived HGF integrates muscle and nerve development during morphogenesis of the mammalian diaphragm

2021 ◽  
Author(s):  
Elizabeth M. Sefton ◽  
Mirialys Gallardo ◽  
Claire E. Tobin ◽  
Mary P. Colasanto ◽  
Gabrielle Kardon
Keyword(s):  
Connective Tissue ◽  
Phrenic Nerve ◽  
Birth Defect ◽  
Diaphragm Muscle ◽  
Coordinated Development ◽  
Pharmacological Inhibition ◽  
Summary Statement ◽  
The Common ◽  
Nerve Development ◽  
Diaphragmatic Hernias

AbstractThe diaphragm is a domed muscle between the thorax and abdomen essential for breathing in mammals. Diaphragm development requires the coordinated development of muscle, connective tissue, and nerve, which are derived from different embryonic sources. Defects in diaphragm development cause the common and often lethal birth defect, Congenital Diaphragmatic Hernias (CDH). HGF/MET signaling is required for diaphragm muscularization, but the source of HGF and the specific functions of this pathway in muscle progenitors or potentially the phrenic nerve have not been explicitly tested. Using conditional mutagenesis and pharmacological inhibition of MET, we demonstrate that the pleuroperitoneal folds (PPFs), transient embryonic structures that give rise to the connective tissue, are the source of HGF critical for diaphragm muscularization and phrenic nerve primary branching. HGF not only is required for recruitment of muscle progenitors to the diaphragm, but is continuously required for maintenance and motility of the pool of progenitors to enable full muscularization. Thus, the connective tissue fibroblasts and HGF coordinately regulate diaphragm muscularization and innervation. Defects in PPF-derived HGF result in muscleless regions that are susceptible to CDH.Summary StatementFibroblast-derived HGF signals to Met+ muscle progenitors and nerve to control the expansion of diaphragm muscle and primary branching of phrenic nerve axons - structures critical for breathing in mammals.

scholarly journals Developmental origin and morphogenesis of the diaphragm, an essential mammalian muscle

2018 ◽  
Author(s):  
Elizabeth M Sefton ◽  
Mirialys Gallardo ◽  
Gabrielle Kardon
Keyword(s):  
Connective Tissue ◽  
Phrenic Nerve ◽  
Leading Edge ◽  
List Type ◽  
Mammalian Skeletal Muscle ◽  
Coordinated Development ◽  
Developmental Origin ◽  
Muscle Nerve ◽  
Axon Projection ◽  
Thoracic And Abdominal

AbstractThe diaphragm is a mammalian skeletal muscle essential for respiration and for separating the thoracic and abdominal cavities. Development of the diaphragm requires the coordinated development of muscle, muscle connective tissue, tendon, nerves, and vasculature that derive from different embryonic sources. However, defects in diaphragm development are common and the cause of an often deadly birth defect, Congenital Diaphragmatic Hernia (CDH). Here we comprehensively describe the normal developmental origin and complex spatial-temporal relationship between the different developing tissues to form a functional diaphragm using a developmental series of mouse embryos genetically and immunofluorescently labeled and analyzed in whole mount. We find that the earliest developmental events are the emigration of muscle progenitors from cervical somites followed by the projection of phrenic nerve axons from the cervical neural tube. Muscle progenitors and phrenic nerve target the pleuroperitoneal folds (PPFs), transient pyramidal-shaped structures that form between the thoracic and abdominal cavities. Subsequently, the PPFs expand across the surface of the liver to give rise to the muscle connective tissue and central tendon, and the leading edge of their expansion precedes muscle morphogenesis, formation of the vascular network, and outgrowth and branching of the phrenic nerve. Thus development and morphogenesis of the PPFs is critical for diaphragm formation. In addition, our data indicate that the earliest events in diaphragm development are critical for the etiology of CDH and instrumental to the evolution of the diaphragm. CDH initiates prior to E12.5 in mouse and suggests that defects in the early PPF formation or their ability to recruit muscle are an important source of CDH. Also, the recruitment of muscle progenitors from cervical somites to the nascent PPFs is uniquely mammalian and a key developmental innovation essential for the evolution of the muscularized diaphragm.HighlightsDiaphragm development begins with emigration of muscle progenitors from cervical somites.Phrenic nerve axons follow muscle path towards nascent pleuroperitoneal folds (PPFs).PPFs are the target of muscle migration and phrenic nerve axon projectionPPF expansion precedes and likely directs muscle, nerve, and vasculature development.Early defects in PPFs and muscle recruitment are likely a source of CDH.

Differential actions of brevetoxin on phrenic nerve and diaphragm muscle in the rat

Toxicon ◽  
1993 ◽  
Vol 31 (4) ◽  
pp. 459-470 ◽  
Author(s):  
Sharad S. Deshpande ◽  
Michael Adler ◽  
Robert E. Sheridan
Keyword(s):  
Phrenic Nerve ◽  
Diaphragm Muscle

The use of methyl green as a histochemical reagent

1965 ◽  
Vol s3-106 (73) ◽  
pp. 3-13
Author(s):  
JOHN R. BAKER ◽  
ELIZABETH G. M. WILLIAMS
Keyword(s):  
Connective Tissue ◽  
Malachite Green ◽  
Helix Aspersa ◽  
Common Snail ◽  
Methyl Green ◽  
Dilute Solution ◽  
Dilute Solutions ◽  
The Common ◽  
Snail Helix Aspersa

The cation of methyl green carriea two poaitive charges, that of malachite green only one; but the two dyes behave towards tissue-constituents in almost exactly the same way. These dyes are not specific for chromatin. They colour certain objects that are devoid of DNA, even when they are used in very dilute solution. The granules of cells called Körnchenzellen in the connective tissue of the common snail, Helix aspersa, are strongly coloured by both dyes from very dilute solutions, and thus provide a striking instance of the unspecificity of these dyes. Malachite green, which is stable and free from contamination by metachromstic impurities, can advantageously replace the methyl green commonly used in mixtures with pyronine. It is suggested that pyronine may have a greater capacity for penetrating into close-textured objects, such ss nucleoli and ribosomes, than methyl and malachite greens.

Visualization of the diaphragm muscle with ultrasound improves diagnostic accuracy of phrenic nerve conduction studies

2014 ◽  
Vol 49 (5) ◽  
pp. 669-675 ◽  
Author(s):  
Nicholas E. Johnson ◽  
Michael Utz ◽  
Erica Patrick ◽  
Nicole Rheinwald ◽  
Marlene Downs ◽  
...  
Keyword(s):  
Diagnostic Accuracy ◽  
Phrenic Nerve ◽  
Nerve Conduction ◽  
Nerve Conduction Studies ◽  
Diaphragm Muscle

Immune and Infectious Diseases

2018 ◽  
pp. 430-470
Author(s):  
Andrea C. Adams
Keyword(s):  
Multiple Sclerosis ◽  
Central Nervous System ◽  
Nervous System ◽  
Young People ◽  
Connective Tissue ◽  
Infectious Diseases ◽  
Temporal Profile ◽  
Immune Mediated ◽  
The Central Nervous System ◽  
The Common

Many immune-mediated diseases and infections affect the central and peripheral nervous systems. The common feature that characterizes both immune-mediated diseases and infections is a subacute temporal profile. Immune-mediated disease can affect only the nervous system or involve the nervous system as part of a systemic illness, as in vasculitis and connective tissue disease. Multiple sclerosis (MS), the most common disabling neurologic illness of young people, is the prototypical immune-mediated disease of the central nervous system (CNS).

scholarly journals Diaphragm neuromuscular transmission failure in aged rats

2019 ◽  
Vol 122 (1) ◽  
pp. 93-104 ◽  
Author(s):  
Matthew J. Fogarty ◽  
Maria A. Gonzalez Porras ◽  
Carlos B. Mantilla ◽  
Gary C. Sieck
Keyword(s):  
Nerve Stimulation ◽  
Phrenic Nerve ◽  
Neuromuscular Transmission ◽  
Motor Units ◽  
Diaphragm Muscle ◽  
Muscle Stimulation ◽  
Transmission Failure ◽  
Old Rats ◽  
Motor Neuron Loss ◽  
Fast Twitch

In aging Fischer 344 rats, phrenic motor neuron loss, neuromuscular junction abnormalities, and diaphragm muscle (DIAm) sarcopenia are present by 24 mo of age, with larger fast-twitch fatigue-intermediate (type FInt) and fast-twitch fatigable (type FF) motor units particularly vulnerable. We hypothesize that in old rats, DIAm neuromuscular transmission deficits are specific to type FInt and/or FF units. In phrenic nerve/DIAm preparations from rats at 6 and 24 mo of age, the phrenic nerve was supramaximally stimulated at 10, 40, or 75 Hz. Every 15 s, the DIAm was directly stimulated, and the difference in forces evoked by nerve and muscle stimulation was used to estimate neuromuscular transmission failure. Neuromuscular transmission failure in the DIAm was observed at each stimulation frequency. In the initial stimulus trains, the forces evoked by phrenic nerve stimulation at 40 and 75 Hz were significantly less than those evoked by direct muscle stimulation, and this difference was markedly greater in 24-mo-old rats. During repetitive nerve stimulation, neuromuscular transmission failure at 40 and 75 Hz worsened to a greater extent in 24-mo-old rats compared with younger animals. Because type IIx and/or IIb DIAm fibers (type FInt and/or FF motor units) display greater susceptibility to neuromuscular transmission failure at higher frequencies of stimulation, these data suggest that the age-related loss of larger phrenic motor neurons impacts nerve conduction to muscle at higher frequencies and may contribute to DIAm sarcopenia in old rats. NEW & NOTEWORTHY Diaphragm muscle (DIAm) sarcopenia, phrenic motor neuron loss, and perturbations of neuromuscular junctions (NMJs) are well described in aged rodents and selectively affect FInt and FF motor units. Less attention has been paid to the motor unit-specific aspects of nerve-muscle conduction. In old rats, increased neuromuscular transmission failure occurred at stimulation frequencies where FInt and FF motor units exhibit conduction failures, along with decreased apposition of pre- and postsynaptic domains of DIAm NMJs of these units.

scholarly journals Anatomical variations of the phrenic nerve: an actualized review

2015 ◽  
Vol 32 (01) ◽  
pp. 053-056 ◽  
Author(s):  
A. Prates Júnior ◽  
L. Vasques ◽  
L. Bordoni
Keyword(s):  
Subclavian Artery ◽  
Phrenic Nerve ◽  
Subclavian Vein ◽  
Internal Thoracic Artery ◽  
Anatomical Variations ◽  
Surgical Anatomy ◽  
Diaphragm Muscle ◽  
Normal Anatomy ◽  
The Subject ◽  
Superior Portion

Abstract Introduction: The phrenic nerve normally arises from ventral rami of C3, C4 and C5. It emerges laterally to the superior portion oflateral border of scalenus anterior muscle and presents a descendent course between subclavian artery and vein. It crosses anterior to internal thoracic artery and descends through the mediastinum, until the diaphragm muscle, to supply it with motor and sensitive fibers. Matherials and Methods: A bibliographic review was conducted, based on anatomy, neuroanatomy and surgical anatomy textbooks, published in Brazil and abroad, as well as a review of scientific articles, published over the last 20 years, available on research databases PubMed, Scielo, LILACS and MEDLINE, from keywords phrenic nerve, variation and anomaly. Results: Variations of the phrenic nerve are frequent, but they are not often discussed. Thus, we aimed to conduct an actualized review over the subject. Regarding the variations in the origin of the phrenic nerve, textbooks vaguely inform that it is mainly formed by C4, but the recent cadaveric studies pointed the segments C4 and C5 as the most common origin. About the variations in its course, the most described is its passage anterior to the subclavian vein, before reaching the thorax. However, the presence of accessory phrenic nerve represents the greatestvariation, mostly arising from nerve to subclavian. There are few reports in literature about the complications associated to these variations, but some are suggested, as the possibility of causing its damage during the puncture of the subclavian vein, when the nerve descends anterior to it, which may lead to a hemidiaphragmatic paresis. When variations are present, even simple procedures may cause injuries. Conclusion: Therefore it is fundamental to know the normal anatomy and the possible variations of the phrenic nerve, in order to perform safe procedures in its topography, as well as to enable a timely recognition of complications.

Response of the diaphragm muscle to electrical stimulation of the phrenic nerve

1983 ◽  
Vol 58 (1) ◽  
pp. 92-100 ◽  
Author(s):  
Thomas E. Ciesielski ◽  
Yoshitaka Fukuda ◽  
William W. L. Glenn ◽  
Jack Gorfien ◽  
Kathryn Jeffery ◽  
...  
Keyword(s):  
Electrical Stimulation ◽  
Phrenic Nerve ◽  
High Frequency ◽  
Low Frequency ◽  
Diaphragm Muscle ◽  
Diaphragm Pacing ◽  
Frequency Group ◽  
Low Frequency Stimulation ◽  
Frequency Stimulation

✓ The histological, histochemical, and ultrastructural features of canine diaphragms subjected to pacing by high-frequency electrical stimulation (27 to 33 Hz) of the phrenic nerve are compared with unstimulated diaphragms and with diaphragms subjected to pacing by low-frequency stimulation (11 to 13 Hz). The high-frequency group showed a reduced tidal volume (fatigue) after long-term stimulation, and myopathic changes which included enlarged internal and sarcolemmal nuclei, ring fibers, moth-eaten fibers with irregular histochemical staining, core/targetoid fibers, and smearing and aggregation of Z-band material with electron microscopy. The low-frequency group did not develop a significant degree of fatigue or pathological changes, and showed histochemical evidence of transformation to fast-twitch (type II) fibers. Possible pathogenic mechanisms and their similarity to those in certain human neuromuscular diseases are discussed. The application of the findings resulting from high- and low-frequency stimulation to long-term diaphragm pacing in humans with chronic ventilatory insufficiency is also discussed.

scholarly journals Diaphragm curvature modulates the relationship between muscle shortening and volume displacement

2011 ◽  
Vol 301 (1) ◽  
pp. R76-R82 ◽  
Author(s):  
Brad J. Greybeck ◽  
Matthew Wettergreen ◽  
Rolf D. Hubmayr ◽  
Aladin M. Boriek
Keyword(s):  
Nerve Stimulation ◽  
Phrenic Nerve ◽  
Spontaneous Breathing ◽  
Three Dimensional ◽  
Diaphragm Muscle ◽  
Phrenic Nerve Stimulation ◽  
Lung Volumes ◽  
Muscle Shortening ◽  
Residual Capacity ◽  
The Relationship

During physiological spontaneous breathing maneuvers, the diaphragm displaces volume while maintaining curvature. However, with maximal diaphragm activation, curvature decreases sharply. We tested the hypotheses that the relationship between diaphragm muscle shortening and volume displacement (VD) is nonlinear and that curvature is a determinant of such a relationship. Radiopaque markers were surgically placed on three neighboring muscle fibers in the midcostal region of the diaphragm in six dogs. The three-dimensional locations were determined using biplanar fluoroscopy and diaphragm VD, curvature, and muscle shortening were computed in the prone and supine postures during spontaneous breathing (SB), spontaneous inspiration efforts after airway occlusion at lung volumes ranging from functional residual capacity (FRC) to total lung capacity, and during bilateral maximal phrenic nerve stimulation at those same lung volumes. In supine dogs, diaphragm VD was approximately two- to three-fold greater during maximal phrenic nerve stimulation than during SB. The contribution of muscle shortening to VD nonlinearly increases with level of diaphragm activation independent of posture. During submaximal diaphragm activation, the contribution is essentially linear due to constancy of diaphragm curvature in both the prone and supine posture. However, the sudden loss of curvature during maximal bilateral phrenic nerve stimulation at muscle shortening values greater than 40% (ΔL/LFRC) causes a nonlinear increase in the contribution of muscle shortening to diaphragm VD, which is concomitant with a nonlinear change in diaphragm curvature. We conclude that the nonlinear relationship between diaphragm muscle shortening and its VD is, in part, due to a loss of its curvature at extreme muscle shortening.

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