scholarly journals Preclinical Advances of Therapies for Laminopathies

2021 ◽  
Vol 10 (21) ◽  
pp. 4834
Author(s):  
Louise Benarroch ◽  
Enzo Cohen ◽  
Antonio Atalaia ◽  
Rabah Ben Yaou ◽  
Gisèle Bonne ◽  
...  
Keyword(s):  
Animal Models ◽  
Striated Muscle ◽  
Accelerated Ageing ◽  
Striated Muscles ◽  
Lmna Gene ◽  
Therapeutic Approaches ◽  
Rare Disorders ◽  
Adipose Tissues ◽  
Gene Therapies ◽  
Strong Focus

Laminopathies are a group of rare disorders due to mutation in LMNA gene. Depending on the mutation, they may affect striated muscles, adipose tissues, nerves or are multisystemic with various accelerated ageing syndromes. Although the diverse pathomechanisms responsible for laminopathies are not fully understood, several therapeutic approaches have been evaluated in patient cells or animal models, ranging from gene therapies to cell and drug therapies. This review is focused on these therapies with a strong focus on striated muscle laminopathies and premature ageing syndromes.

NMDA Antagonist Peptide Supplementation Enhances Pain Alleviation by Adrenal Medullary Transplants

2005 ◽  
Vol 14 (4) ◽  
pp. 203-211 ◽  
Author(s):  
Farinaz Nasirinezhad ◽  
Jacqueline Sagen
Keyword(s):  
Neuropathic Pain ◽  
Animal Models ◽  
Striated Muscle ◽  
Thermal Hyperalgesia ◽  
Nmda Antagonist ◽  
Nmda Receptor Antagonist ◽  
Intraplantar Injection ◽  
Amino Acid Peptide ◽  
Spinal Subarachnoid Space ◽  
Pain Symptoms

Spinal transplantation of adrenal medullary chromaffin cells has been shown to decrease pain responses in several animal models. Improved potency may be possible by engineering cells to produce greater levels of naturally derived analgesics. As an initial screen for potential candidates, adrenal medullary transplants were evaluated in combination with exogenously administered neuropeptides in rodent pain models. Histogranin is a 15-amino acid peptide that exhibits NMDA receptor antagonist activity. The stable derivative [Ser1]histogranin (SHG) can attenuate pain symptoms in some animal models. The formalin model for neurogenic inflammatory pain and the chronic constriction injury (CCI) model for neuropathic pain were used to evaluate the combined effects of chromaffin cell transplantation and intrathecal (IT) SHG injections. Animals were implanted with either adrenal medullary or control striated muscle tissue in the spinal subarachnoid space. For evaluation of formalin responses, animals were pretreated with SHG (0.5, 1.0, 3.0 μg) followed by an intraplantar injection of formalin, and flinching responses were quantified. Pretreatment with SHG had no significant effect on flinching behavior in control animals at lower doses, with incomplete attenuation only at the highest dose. In contrast, 0.5 μg SHG significantly reduced flinching responses in animals with adrenal medullary transplants, and 1.0 μg nearly completely eliminated flinching in these animals in the tonic phase. For evaluation of effects on neuropathic pain, animals received transplants 1 week following CCI, and were tested for thermal and mechanical hyperalgesia and cold allodynia before and following SHG treatment. The addition of low doses of SHG nearly completely eliminated neuropathic pain symptoms in adrenal medullary transplanted animals, while in control transplanted animals only thermal hyperalgesia was attenuated, at the highest dose of SHG. These results suggest that SHG can augment adrenal medullary transplants, and the combination may result in improved effectiveness and range in the treatment of chronic pain syndromes.

Phylogenetic implications of the superfast myosin in extraocular muscles

2002 ◽  
Vol 205 (15) ◽  
pp. 2189-2201 ◽  
Author(s):  
Fred Schachat ◽  
Margaret M. Briggs
Keyword(s):  
Myosin Heavy Chain ◽  
Gene Cluster ◽  
Heavy Chain ◽  
Striated Muscle ◽  
Extraocular Muscles ◽  
Chromosome 17 ◽  
Striated Muscles ◽  
Chromosome 11 ◽  
Phylogenetic Implications ◽  
Myh Gene

SUMMARY Extraocular muscle exhibits higher-velocity and lower-tension contractions than other vertebrate striated muscles. These distinctive physiological properties are associated with the expression of a novel extraocular myosin heavy chain (MYH). Encoded by the MYH13 gene, the extraocular myosin heavy chain is a member of the fast/developmental MYH gene cluster on human chromosome 17 and the syntenic MYH cluster on mouse chromosome 11. Comparison of cDNA sequences reveals that MYH13 also encodes the atypical MYH identified in laryngeal muscles, which have similar fast contractile properties. Comparing the MYH13 sequence with the other members of the fast/developmental cluster, the slow/cardiac MYH genes and two orphan skeletal MYH genes in the human genome provides insights into the origins of specialization in striated muscle myosins. Specifically, these studies indicate (i) that the extraocular myosin is not derived from the adult fast skeletal muscle myosins, but was the first member of the fast/developmental MYH gene cluster to diverge and specialize, (ii) that the motor and rod domains of the MYH13 have evolved under different selective pressures and (iii) that the MYH13 gene has been largely insulated from genomic events that have shaped other members of the fast/developmental cluster. In addition, phylogenetic footprinting suggests that regulation of the extraocular MYH gene is not governed primarily by myogenic factors, but by a hierarchical network of regulatory factors that relate its expression to the development of extraocular muscles.

scholarly journals Therapeutic Effects of Hydrogen in Animal Models of Parkinson's Disease

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Kyota Fujita ◽  
Yusaku Nakabeppu ◽  
Mami Noda
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Animal Models ◽  
Animal Studies ◽  
Clinical Symptoms ◽  
Therapeutic Effects ◽  
Therapeutic Approaches ◽  
Cellular Apoptosis ◽  
6 Hydroxydopamine

Since the first description of Parkinson's disease (PD) nearly two centuries ago, a number of studies have revealed the clinical symptoms, pathology, and therapeutic approaches to overcome this intractable neurodegenerative disease. 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) are neurotoxins which produce Parkinsonian pathology. From the animal studies using these neurotoxins, it has become well established that oxidative stress is a primary cause of, and essential for, cellular apoptosis in dopaminergic neurons. Here, we describe the mechanism whereby oxidative stress evokes irreversible cell death, and propose a novel therapeutic strategy for PD using molecular hydrogen. Hydrogen has an ability to reduce oxidative damage and ameliorate the loss of nigrostriatal dopaminergic neuronal pathway in two experimental animal models. Thus, it is strongly suggested that hydrogen might provide a great advantage to prevent or minimize the onset and progression of PD.

scholarly journals A distinct cardiopharyngeal mesoderm genetic hierarchy establishes antero-posterior patterning of esophagus striated muscle

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Glenda Comai ◽  
Eglantine Heude ◽  
Sebastian Mella ◽  
Sylvain Paisant ◽  
Francesca Pala ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Striated Muscle ◽  
Striated Muscles ◽  
Food Ingestion ◽  
Loss Of Function ◽  
Pharmacological Studies ◽  
Posterior Migration ◽  
Functional Relevance ◽  
Genetic Signatures ◽  
Genetic Hierarchy

In most vertebrates, the upper digestive tract is composed of muscularized jaws linked to the esophagus that permits food ingestion and swallowing. Masticatory and esophagus striated muscles (ESM) share a common cardiopharyngeal mesoderm (CPM) origin, however ESM are unusual among striated muscles as they are established in the absence of a primary skeletal muscle scaffold. Using mouse chimeras, we show that the transcription factors Tbx1 and Isl1 are required cell-autonomously for myogenic specification of ESM progenitors. Further, genetic loss-of-function and pharmacological studies point to MET/HGF signaling for antero-posterior migration of esophagus muscle progenitors, where Hgf ligand is expressed in adjacent smooth muscle cells. These observations highlight the functional relevance of a smooth and striated muscle progenitor dialogue for ESM patterning. Our findings establish a Tbx1-Isl1-Met genetic hierarchy that uniquely regulates esophagus myogenesis and identify distinct genetic signatures that can be used as framework to interpret pathologies arising within CPM derivatives.

The superfast extraocular myosin (MYH13) is localized to the innervation zone in both the global and orbital layers of rabbit extraocular muscle

2002 ◽  
Vol 205 (20) ◽  
pp. 3133-3142 ◽  
Author(s):  
Margaret M. Briggs ◽  
Fred Schachat
Keyword(s):  
Eye Movements ◽  
Striated Muscle ◽  
Contractile Activity ◽  
Regional Distribution ◽  
Motor Units ◽  
Molecular Heterogeneity ◽  
Ocular Motility ◽  
Fiber Types ◽  
Striated Muscles ◽  
Innervation Zone

SUMMARY Extraocular muscles (EOMs) are the most molecularly heterogeneous and physiologically diverse mammalian striated muscles. They express the entire array of striated muscle myosins, including a specialized myosin heavy chain MYH13, which is restricted to extraocular and laryngeal muscles. EOMs also exhibit a breadth of contractile activity, from superfast saccades to slow tracking and convergence movements. These movements are accomplished by the action of six ultrastructurally defined fiber types that differ from the type IIa, IIb, IIx and I fibers found in other skeletal muscles. Attempts to associate different eye movements with either the expression of different myosins or the activity of particular EOM fiber types are complicated by the molecular heterogeneity of several of the fiber types, and by electromyography studies showing that the majority of extraocular motor units participate in both fast and slow eye movements. To better understand the role of MYH13 in ocular motility, we generated MYH13-sequence-specific antibodies and used SDS-PAGE to quantify the regional distribution of myosin in EOM and to characterize its heterogeneity in single fibers. These studies demonstrate that MYH13 is preferentially expressed in the majority of orbital and global fibers in the central innervation zone of rabbit EOM. Many individual fibers express MYH13 with the fast IIb myosin and varying amounts of IIx myosin. The differential localization of MYH13, coupled with specialization of the sarcoplasmic reticulum and thin filament systems, probably explains how activation of the endplate band region enables the majority of EOM fibers to contribute to superfast contractions.

Caenorhabditis elegans twist plays an essential role in non-striated muscle development

Development ◽  
2000 ◽  
Vol 127 (10) ◽  
pp. 2041-2051 ◽  
Author(s):  
A.K. Corsi ◽  
S.A. Kostas ◽  
A. Fire ◽  
M. Krause
Keyword(s):  
Caenorhabditis Elegans ◽  
Essential Role ◽  
Muscle Development ◽  
Target Genes ◽  
Striated Muscle ◽  
Egg Laying ◽  
Bhlh Transcription Factor ◽  
Striated Muscles ◽  
Downstream Target ◽  
Mesodermal Development

The basic helix-loop-helix (bHLH) transcription factor Twist plays a role in mesodermal development in both invertebrates and vertebrates. In an effort to understand the role of the unique Caenorhabditis elegans Twist homolog, hlh-8, we analyzed mesodermal development in animals with a deletion in the hlh-8 locus. This deletion was predicted to represent a null allele because the HLH domain is missing and the reading frame for the protein is disrupted. Animals lacking CeTwist function were constipated and egg-laying defective. Both of these defects were rescued in transgenic mutant animals expressing wild-type hlh-8. Observing a series of mesoderm-specific markers allowed us to characterize the loss of hlh-8 function more thoroughly. Our results demonstrate that CeTwist performs an essential role in the proper development of a subset of mesodermal tissues in C. elegans. We found that CeTwist was required for the formation of three out of the four non-striated enteric muscles born in the embryo. In contrast, CeTwist was not required for the formation of the embryonically derived striated muscles. Most of the post-embryonic mesoderm develops from a single lineage. CeTwist was necessary for appropriate patterning in this lineage and was required for expression of two downstream target genes, but was not required for the expression of myosin, a marker of differentiation. Our results suggest that mesodermal patterning by Twist is an evolutionarily conserved function.

scholarly journals Gene Therapy for Pancreatic Diseases: Current Status

2018 ◽  
Vol 19 (11) ◽  
pp. 3415 ◽  
Author(s):  
Kenya Kamimura ◽  
Takeshi Yokoo ◽  
Shuji Terai
Keyword(s):  
Pancreatic Cancer ◽  
The Body ◽  
Therapeutic Options ◽  
Current Status ◽  
Endocrine Tumors ◽  
Therapeutic Approaches ◽  
Islet Cell Tumors ◽  
Pancreatic Diseases ◽  
Gene Therapies ◽  
New Strategies

The pancreas is a key organ involved in digestion and endocrine functions in the body. The major diseases of the pancreas include pancreatitis, pancreatic cancer, cystic diseases, pancreatic divisum, islet cell tumors, endocrine tumors, diabetes mellitus, and pancreatic pain induced by these diseases. While various therapeutic methodologies have been established to date, however, the improvement of conventional treatments and establishment of novel therapies are essential to improve the efficacy. For example, conventional therapeutic options, including chemotherapy, are not effective against pancreatic cancer, and despite improvements in the last decade, the mortality rate has not declined and is estimated to become the second cause of cancer-related deaths by 2030. Therefore, continuous efforts focus on the development of novel therapeutic options. In this review, we will summarize the progress toward the development of gene therapies for pancreatic diseases, with an emphasis on recent preclinical studies and clinical trials. We aim to identify new areas for improvement of the current methodologies and new strategies that will lead to safe and effective gene therapeutic approaches in pancreatic diseases.

scholarly journals Morphological changes in the fast vs slow fiber profiles of the urethras of diabetic pregnant rats

2011 ◽  
Vol 25 (1) ◽  
pp. 9 ◽  
Author(s):  
Gabriela Marini ◽  
Angélica M. Pascon Barbosa ◽  
Débora C. Damasceno ◽  
Selma M. Michelin Matheus ◽  
Rodrigo De Aquino Castro ◽  
...  
Keyword(s):  
Striated Muscle ◽  
Morphological Changes ◽  
Fiber Type ◽  
Normal Function ◽  
Striated Muscles ◽  
Pregnant Rats ◽  
Morphological Alterations ◽  
Female Wistar Rats ◽  
Urethral Striated Muscle ◽  
Diabetes And Pregnancy

<em>Background</em>. This study was undertaken to test the hypothesis that diabetes and pregnancy detrimentally affect the normal function of urethral striated muscles in rats, providing a model for additional studies related to urinary incontinence. The aim of this study was to evaluate morphological alterations in the urethral striated muscles of diabetic pregnant rats. <em>Design and methods. </em>Twenty female Wistar rats were distributed into four experimental groups of five rats as follows: virgin, pregnant, diabetic virgin, and diabetic pregnant. Diabetes was induced using streptozotocin administration (40 mg/kg i.v.). The rats were lethally anesthetized, and the urethra and vagina were extracted as a unit. Cryostat sections (6 µm thick) were cut and stained with hematoxylin-eosin, and immunohistochemical procedures were performed and subjected to morphological and semi quantitative analysis. <em>Results</em>. The urethral striated muscle from the diabetic pregnant rats presented with the following variations: thinning and atrophy, disorganization and disruption associated with the colocalization of fast and slow fibers and a steady decrease in the proportion of fast <em>vs</em> slow fibers. <em>Conclusion</em>. Diabetes and pregnancy impair the urethral striated muscle and alter its fiber type distribution.

scholarly journals Cellular and Animal Models of Striated Muscle Laminopathies

Cells ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 291 ◽  
Author(s):  
Hannah A. Nicolas ◽  
Marie-Andrée Akimenko ◽  
Frédérique Tesson
Keyword(s):  
Skeletal Muscle ◽  
Skeletal Muscles ◽  
Molecular Mechanisms ◽  
Striated Muscle ◽  
Nuclear Lamina ◽  
The Other ◽  
Lamin A ◽  
Lmna Gene ◽  
Future Directions ◽  
Exon 10

The lamin A/C (LMNA) gene codes for nuclear intermediate filaments constitutive of the nuclear lamina. LMNA has 12 exons and alternative splicing of exon 10 results in two major isoforms—lamins A and C. Mutations found throughout the LMNA gene cause a group of diseases collectively known as laminopathies, of which the type, diversity, penetrance and severity of phenotypes can vary from one individual to the other, even between individuals carrying the same mutation. The majority of the laminopathies affect cardiac and/or skeletal muscles. The underlying molecular mechanisms contributing to such tissue-specific phenotypes caused by mutations in a ubiquitously expressed gene are not yet well elucidated. This review will explore the different phenotypes observed in established models of striated muscle laminopathies and their respective contributions to advancing our understanding of cardiac and skeletal muscle-related laminopathies. Potential future directions for developing effective treatments for patients with lamin A/C mutation-associated cardiac and/or skeletal muscle conditions will be discussed.

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