Desmin knockout muscles generate lower stress and are less vulnerable to injury compared with wild-type muscles

2000 ◽  
Vol 279 (4) ◽  
pp. C1116-C1122 ◽  
Author(s):  
Michel Sam ◽  
Sameer Shah ◽  
Jan Fridén ◽  
Derek J. Milner ◽  
Yassemi Capetanaki ◽  
...  
Keyword(s):  
Intermediate Filament ◽  
Muscle Force ◽  
Mechanical Energy ◽  
Eccentric Contraction ◽  
Null Mouse ◽  
Wild Type ◽  
Lower Stress ◽  
Filament System ◽  
Muscle Types

The functional role of the skeletal muscle intermediate filament system was investigated by measuring the magnitude of muscle force loss after cyclic eccentric contraction (EC) in normal and desmin null mouse extensor digitorum longus muscles. Isometric stress generated was significantly greater in wild-type (313 ± 8 kPa) compared with knockout muscles (276 ± 13 kPa) before EC ( P < 0.05), but 1 h after 10 ECs, both muscle types generated identical levels of stress (∼250 kPa), suggesting less injury to the knockout. Differences in injury susceptibility were not explained by the different absolute stress levels imposed on wild-type versus knockout muscles (determined by testing older muscles) or by differences in fiber length or mechanical energy absorbed. Morphometric analysis of longitudinal electron micrographs indicated that Z disks from knockout muscles were more staggered (0.36 ± 0.03 μm) compared with wild-type muscles (0.22 ± 0.03 μm), which may indicate that the knockout cytoskeleton is more compliant. These data demonstrate that lack of the intermediate filament system decreases isometric stress production and that the desmin knockout muscle is less vulnerable to mechanical injury.

scholarly journals Depletion of Cholesteryl Esters Causes Meibomian Gland Dysfunction-Like Symptoms in a Soat1-Null Mouse Model

2021 ◽  
Vol 22 (4) ◽  
pp. 1583
Author(s):  
Igor A. Butovich ◽  
Amber Wilkerson ◽  
Seher Yuksel
Keyword(s):  
Mouse Model ◽  
High Resolution Mass Spectrometry ◽  
Meibomian Gland ◽  
Lipid Homeostasis ◽  
Null Mouse ◽  
Complete Suppression ◽  
Cholesteryl Esters ◽  
Wild Type ◽  
Massive Accumulation

Previous studies on ablation of several key genes of meibogenesis related to fatty acid elongation, omega oxidation, and esterification into wax esters have demonstrated that inactivation of any of them led to predicted changes in the meibum lipid profiles and caused severe abnormalities in the ocular surface and Meibomian gland (MG) physiology and morphology. In this study, we evaluated the effects of Soat1 ablation that were expected to cause depletion of the second largest class of Meibomian lipids (ML)—cholesteryl esters (CE)—in a mouse model. ML of the Soat1-null mice were examined using liquid chromatography high-resolution mass spectrometry and compared with those of Soat1+/− and wild-type mice. Complete suppression of CE biosynthesis and simultaneous accumulation of free cholesterol (Chl) were observed in Soat1-null mice, while Soat1+/− mutants had normal Chl and CE profiles. The total arrest of the CE biosynthesis in response to Soat1 ablation transformed Chl into the dominant lipid in meibum accounting for at least 30% of all ML. The Soat1-null mice had clear manifestations of dry eye and MG dysfunction. Enrichment of meibum with Chl and depletion of CE caused plugging of MG orifices, increased meibum rigidity and melting temperature, and led to a massive accumulation of lipid deposits around the eyes of Soat1-null mice. These findings illustrate the role of Soat1/SOAT1 in the lipid homeostasis and pathophysiology of MG.

scholarly journals The Anatomical Distribution of Mechanoreceptors in Mouse Hind Paw Skin and the Influence of Integrin α1β1 on Meissner-Like Corpuscle Density in the Footpads

2021 ◽  
Vol 15 ◽  
Author(s):  
Valerie Wai ◽  
Lauren Roberts ◽  
Jana Michaud ◽  
Leah R. Bent ◽  
Andrea L. Clark
Keyword(s):  
Sensory Feedback ◽  
Receptive Fields ◽  
Glabrous Skin ◽  
Null Mouse ◽  
Merkel Cells ◽  
Wild Type ◽  
Anatomical Distribution ◽  
Footfall Patterns

Afferent neurons and their mechanoreceptors provide critical sensory feedback for gait. The anatomical distribution and density of afferents and mechanoreceptors influence sensory feedback, as does mechanoreceptor function. Electrophysiological studies of hind paw skin reveal the different types of afferent responses and their receptive fields, however, the anatomical distribution of mechanoreceptor endings is unknown. Also, the role of integrin α1β1 in mechanoreceptor function is unclear, though it is expressed by keratinocytes in the stratum basale where it is likely involved in a variety of mechanotransduction pathways and ion channel functionalities. For example, it has been shown that integrin α1β1 is necessary for the function of TRPV4 that is highly expressed by afferent units. The purpose of this study, therefore, was to determine and compare the distribution of mechanoreceptors across the hind paw skin and the footfall patterns of itga1-null and wild type mice. The itga1-null mouse is lacking the integrin α1 subunit, which binds exclusively to the β1 subunit, thus rendering integrin α1β1 nonfunctional while leaving the numerous other pairings of the β1 subunit undisturbed. Intact hind paws were processed, serially sectioned, and stained to visualize mechanoreceptors. Footfall patterns were analyzed as a first step in correlating mechanoreceptor distribution and functionality. Merkel cells and Meissner-like corpuscles were present, however, Ruffini endings and Pacinian corpuscles were not observed. Meissner-like corpuscles were located exclusively in the glabrous skin of the footpads and digit tips, however, Merkel cells were found throughout hairy and glabrous skin. The increased density of Merkel cells and Meissner-like corpuscles in footpads 1 and 3 and Meissner-like corpuscles in footpad 4 suggests their role in anteroposterior balance, while Meissner-like corpuscle concentrations in digits 2 and 5 support their role in mediolateral balance. Finally, a larger density of Meissner-like corpuscles in footpads 3 and 4 in male itga1-null mice compared to wild type controls paves the way for future site-specific single fiber in vivo recordings to provide insight into the role of integrin α1β1 in tactile mechanotransduction.

Renal gene expression profiling using kinin B1 and B2 receptor knockout mice reveals comparable modulation of functionally related genes

2006 ◽  
Vol 387 (1) ◽  
pp. 15-22 ◽  
Author(s):  
Dimcho Bachvarov ◽  
Magdalena Bachvarova ◽  
Rainelli Koumangaye ◽  
Julie Klein ◽  
João Bosco Pesquero ◽  
...  
Keyword(s):  
Gene Expression ◽  
Biological Effects ◽  
Renal Physiology ◽  
Null Mouse ◽  
Biological Processes ◽  
Wild Type ◽  
Microarray Experiments ◽  
B1 Receptor ◽  
Pathological Conditions

Abstract The kinin B2 receptor, which is constitutively expressed in a large number of tissues, mediates most of the known effects of bradykinin (BK). Normally undetectable in healthy tissues, the B1 receptor is strongly over-expressed under pathological conditions. BK is an important mediator in renal homeostasis and is mainly known for its natriuretic and vasodilatory effects. Recent data evidenced a role for BK in many other biological processes, such as apoptosis, development, extracellular matrix regulation and angiogenesis. In a first step to better understand how BK and its receptors could be involved in such a large variety of biological effects, we used microarray analysis to identify, under physiological conditions, the global renal gene expression profile in mice lacking either the kinin B1 or B2 receptor. Microarray experiments were performed using Agilent Mouse Oligonucleotide Microarrays (21 000 genes/microarray). Interestingly, there was a considerable number of mostly downregulated genes in both BK null mouse models compared with wild-type mice. Furthermore, a number of genes that are known to be implicated in renal physiology and/or pathology were differentially expressed in the BK null mice, which is indicative of the important role of both BK receptors in renal function.

scholarly journals Structurally Normal Corneas in Aldehyde Dehydrogenase 3a1-Deficient Mice

2002 ◽  
Vol 22 (3) ◽  
pp. 849-855 ◽  
Author(s):  
David W. Nees ◽  
Eric F. Wawrousek ◽  
W. Gerald Robison ◽  
Joram Piatigorsky
Keyword(s):  
Protein Content ◽  
Corneal Epithelium ◽  
Soluble Protein ◽  
Water Soluble ◽  
Null Mouse ◽  
Wild Type ◽  
Water Soluble Protein ◽  
Slit Lamp Microscopy ◽  
Deficient Mice

ABSTRACT We have constructed an ALDH3a1 null mouse to investigate the role of this enzyme that comprises nearly one-half of the total water-soluble protein in the mouse corneal epithelium. ALDH3a1-deficient mice are viable and fertile, have a corneal epithelium with a water-soluble protein content approximately half that of wild-type mice, and contain no ALDH3a1 as determined by zymograms and immunoblots. Despite the loss of protein content and ALDH3a1 activity, the ALDH3a1−/− mouse corneas appear indistinguishable from wild-type corneas when examined by histological analysis and electron microscopy and are transparent as determined by light and slit lamp microscopy. There is no evidence for a compensating protein or enzyme. Even though the function of ALDH3a1 in the mouse cornea remains unknown, our data indicate that its enzymatic activity is unnecessary for corneal clarity and maintenance, at least under laboratory conditions.

scholarly journals Intermediate filaments in smooth muscle

2008 ◽  
Vol 294 (4) ◽  
pp. C869-C878 ◽  
Author(s):  
Dale D. Tang
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Intermediate Filaments ◽  
Intermediate Filament ◽  
Mammalian Cells ◽  
Muscle Force ◽  
Biological Properties ◽  
External Stimulation ◽  
Force Development

The intermediate filament (IF) network is one of the three cytoskeletal systems in smooth muscle. The type III IF proteins vimentin and desmin are major constituents of the network in smooth muscle cells and tissues. Lack of vimentin or desmin impairs contractile ability of various smooth muscle preparations, implying their important role for smooth muscle force development. The IF framework has long been viewed as a fixed cytostructure that solely provides mechanical integrity for the cell. However, recent studies suggest that the IF cytoskeleton is dynamic in mammalian cells in response to various external stimulation. In this review, the structure and biological properties of IF proteins in smooth muscle are summarized. The role of IF proteins in the modulation of smooth muscle force development and redistribution/translocation of signaling partners (such as p130 Crk-associated substrate, CAS) is depicted. This review also summarizes our latest understanding on how the IF network may be regulated in smooth muscle.

Differential response of TIMP-3 null mice to the lung insults of sepsis, mechanical ventilation, and hyperoxia

2005 ◽  
Vol 289 (2) ◽  
pp. L244-L251 ◽  
Author(s):  
Erica L. Martin ◽  
Lynda A. McCaig ◽  
Brent Z. Moyer ◽  
M. Cynthia Pape ◽  
Kevin J. Leco ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Cecal Ligation ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Null Mouse ◽  
Similar Response ◽  
Wild Type ◽  
Air Space ◽  
Different Types ◽  
Insight Into

An imbalance in matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs) leads to excessive or insufficient tissue breakdown, which is associated with many disease processes. The TIMP-3 null mouse is a model of MMP/TIMP imbalance, which develops air space enlargement and decreased lung function. These mice responded differently to cecal ligation and perforation (CLP)-induced septic lung injury than wild-type controls. The current study addresses whether the TIMP-3 knockout lung is susceptible to different types of insults or only those involving sepsis, by examining its response to lipopolysaccharide (LPS)-induced sepsis, mechanical ventilation (MV), and hyperoxia. TIMP-3 null noninjured controls of each insult consistently demonstrated significantly higher compliance vs. wild-type mice. Null mice treated with LPS had a further significantly increased compliance compared with untreated controls. Conversely, MV and hyperoxia did not alter compliance in the null lung. MMP abundance and activity increased in response to LPS but were generally unaltered following MV or hyperoxia, correlating with compliance alterations. All three insults produced inflammatory cytokines; however, the response of the null vs. wild-type lung was dependent on the type of insult. Overall, this study demonstrated that 1) LPS-induced sepsis produced a similar response in null mice to CLP-induced sepsis, 2) the null lung responded differently to various insults, and 3) the null susceptibility to compliance changes correlated with increased MMPs. In conclusion, this study provides insight into the role of TIMP-3 in response to various lung insults, specifically its importance in regulating MMPs to maintain compliance during a sepsis.

scholarly journals Novel roles for erythroid Ankyrin-1 revealed through an ENU-induced null mouse mutant

Blood ◽  
2009 ◽  
Vol 113 (14) ◽  
pp. 3352-3362 ◽  
Author(s):  
Gerhard Rank ◽  
Rosemary Sutton ◽  
Vikki Marshall ◽  
Rachel J. Lundie ◽  
Jacinta Caddy ◽  
...  
Keyword(s):  
Null Mouse ◽  
Red Cell ◽  
Wild Type ◽  
Ideal Model ◽  
Red Cell Membrane ◽  
Tissue Iron ◽  
Red Cell Survival ◽  
Hypomorphic Alleles ◽  
Erythroid Development

AbstractInsights into the role of ankyrin-1 (ANK-1) in the formation and stabilization of the red cell cytoskeleton have come from studies on the nb/nb mice, which carry hypomorphic alleles of Ank-1. Here, we revise several paradigms established in the nb/nb mice through analysis of an N-ethyl-N-nitrosourea (ENU)–induced Ank-1–null mouse. Mice homozygous for the Ank-1 mutation are profoundly anemic in utero and most die perinatally, indicating that Ank-1 plays a nonredundant role in erythroid development. The surviving pups exhibit features of severe hereditary spherocytosis (HS), with marked hemolysis, jaundice, compensatory extramedullary erythropoiesis, and tissue iron overload. Red cell membrane analysis reveals a complete loss of ANK-1 protein and a marked reduction in β-spectrin. As a consequence, the red cells exhibit total disruption of cytoskeletal architecture and severely altered hemorheologic properties. Heterozygous mutant mice, which have wild-type levels of ANK-1 and spectrin in their RBC membranes and normal red cell survival and ultrastructure, exhibit profound resistance to malaria, which is not due to impaired parasite entry into RBC. These findings provide novel insights into the role of Ank-1, and define an ideal model for the study of HS and malarial resistance.

scholarly journals Strain-Dependent Influences on the Hypothalamo-Pituitary-Adrenal Axis Profoundly Affect the 7B2 and PC2 Null Phenotypes

Endocrinology ◽  
2005 ◽  
Vol 146 (8) ◽  
pp. 3438-3444 ◽  
Author(s):  
Juan R. Peinado ◽  
Virginie Laurent ◽  
Sang-Nam Lee ◽  
Bonnie W. Peng ◽  
John E. Pintar ◽  
...  
Keyword(s):  
Null Mouse ◽  
Wild Type ◽  
Acth Stimulation ◽  
Phenotypic Differences ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Phenotype Characteristic ◽  
Strain Dependent ◽  
Pituitary Adrenal Axis

Abstract Two null mouse models have previously been created to study the role of the prohormone convertase (PC2) and its helper protein 7B2; unexpectedly, the phenotypes of these two nulls differ profoundly, with the 7B2 but not the PC2 null dying at 5 wk. The genetic backgrounds of these two models differ, with the 7B2 null in a 129/SvEv (129) background and the PC2 null in a mixed C57BL/N6:129/SvEv (B6:129) background. Because background can contribute greatly to phenotype, we have here examined strain influence on the hypothalamo-pituitary-adrenal (HPA) axis and glucose levels in wild-type, 7B2 null, and PC2 null mice. Wild-type B6 and 129 mice differed in basal corticosterone and glucose levels. When 7B2 nulls were transferred onto the B6 background, they survived and showed greatly decreased circulating corticosterone and increased blood glucose levels, most likely due to the comparatively higher adrenal resistance of the B6 strain to ACTH stimulation. Circulating ACTH levels were increased over wild-type in the B6 7B2 null but did not reach levels as high as the 129 7B2 null. Conversely, when the mixed-strain PC2 nulls were bred into the 129 background at the N6 generation, they began to exhibit the Cushing’s-like phenotype characteristic of 129 7B2 null mice and died before 6 wk of age. Taken together, these results indicate that background effects are critical because they increase the phenotypic differences between the 7B2 and PC2 nulls and play a life-or-death role in the ACTH hypersecretion syndrome present in both 129 nulls.

scholarly journals Sarcomere number regulation maintained after immobilization in desmin-null mouse skeletal muscle

2001 ◽  
Vol 204 (10) ◽  
pp. 1703-1710 ◽  
Author(s):  
S.B. Shah ◽  
D. Peters ◽  
K.A. Jordan ◽  
D.J. Milner ◽  
J. Friden ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Knockout Mice ◽  
Tibialis Anterior ◽  
Null Mouse ◽  
Wild Type ◽  
Optimal Arrangement ◽  
Hindlimb Muscles ◽  
Muscle Changes ◽  
Sarcomere Number

The serial sarcomere number of skeletal muscle changes in response to chronic length perturbation. The role of the intermediate filament desmin in regulating these changes was investigated by comparing the architectural adaptations of the tibialis anterior, extensor digitorum longus (EDL) and soleus from wild-type mice with those of homozygous desmin knockout mice after hindlimb immobilization. After 28 days, serial sarcomere number increased significantly in the lengthened wild-type tibialis anterior (by approximately 9 %) and EDL (by approximately 17 %). Surprisingly, muscles from desmin knockout mice also experienced significant serial remodeling, with the serial sarcomere number of the tibialis anterior increasing by approximately 10 % and that of the EDL by approximately 27 %. A consistent result was observed in the shortened soleus: a significant decrease in sarcomere number was observed in the muscles from both wild-type (approximately 26 %) and knockout (approximately 12 %) mice. Thus, although desmin is not essential for sarcomerogenesis or sarcomere subtraction in mouse hindlimb muscles, the results do suggest subtle differences in the nature of sarcomere number adaptation. We speculate that desmin may play a role in regulating the optimal arrangement of sarcomeres within the muscle or in sensing the magnitude of the immobilization effect itself.

An immunoelectron microscopic examination of the intermediate filament protein, desmin, in exercise-damaged skeletal muscle

1991 ◽  
Vol 49 ◽  
pp. 14-15
Author(s):  
C.M. Waterman-Storer
Keyword(s):  
Skeletal Muscle ◽  
Eccentric Exercise ◽  
Intermediate Filament ◽  
Intermediate Filament Protein ◽  
Tension Development ◽  
Filament System ◽  
Exercise Muscle ◽  
Exercise Induced ◽  
Filament Protein

Intense exercise has been shown to produce pathological changes in normal skeletal muscle ultrastructure. Eccentric exercise (muscle lengthening during active tension development) in particular has been shown to cause the most severe muscle damage, and studies of both human and animal tissue following eccentric exercise have documented disruption to the contractile apparatus. The disruption originates at the Z-disc, which appears broadened, smeared, or totally disrupted, with Z-discs of adjacent myofibrils out of register and running a “zig-zag” course transversely across the fiber. This condition is known as Z-line streaming. Several researchers have implicated the disruption of the intermediate filament system in the etiology of exercise-induced Z-line streaming, as these filaments are believed to link adjacent myofibrils at the level of the Z-disc. The intermediate filaments are composed predominantly of the proteins desmin and vimentin. This study utilized immunoelectron microscopic localization of desmin in order to elucidate the role of the intermediate filament system in Zline streaming of eccentrically-exercised skeletal muscle.

Sign in / Sign up

Export Citation Format

Share Document