scholarly journals Gene therapy for overexpressing Neuregulin 1 type I in skeletal muscles promotes functional improvement in the SOD1G93A ALS mice

2020 ◽  
Vol 137 ◽  
pp. 104793
Author(s):  
Guillem Mòdol-Caballero ◽  
Mireia Herrando-Grabulosa ◽  
Belén García-Lareu ◽  
Neus Solanes ◽  
Sergi Verdés ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Skeletal Muscles ◽  
Functional Improvement ◽  
Type I ◽  
Neuregulin 1

scholarly journals Gene Therapy Overexpressing Neuregulin 1 Type I in Combination With Neuregulin 1 Type III Promotes Functional Improvement in the SOD1G93A ALS Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Guillem Mòdol-Caballero ◽  
Mireia Herrando-Grabulosa ◽  
Sergi Verdés ◽  
Belén García-Lareu ◽  
Neus Hernández ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Gene Therapy ◽  
Skeletal Muscles ◽  
Viral Vectors ◽  
Neuromuscular Junctions ◽  
Functional Improvement ◽  
Type I ◽  
Neuregulin 1 ◽  
Beneficial Effects ◽  
The Central Nervous System

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting the neuromuscular system for which currently there is no effective therapy. Motoneuron (MN) degeneration involves several complex mechanisms, including surrounding glial cells and skeletal muscle contributions. Neuregulin 1 (NRG1) is a trophic factor present particularly in MNs and neuromuscular junctions. Our previous studies revealed that gene therapy overexpressing the isoform I (NRG1-I) in skeletal muscles as well as overexpressing the isoform III (NRG1-III) directly in the central nervous system are both effective in preserving MNs in the spinal cord of ALS mice, opening novel therapeutic approaches. In this study, we combined administration of both viral vectors overexpressing NRG1-I in skeletal muscles and NRG1-III in spinal cord of the SOD1G93A mice in order to obtain a synergistic effect. The results showed that the combinatorial gene therapy increased preservation of MNs and of innervated neuromuscular junctions and reduced glial reactivity in the spinal cord of the treated SOD1G93A mice. Moreover, NRG1 isoforms overexpression improved motor function of hindlimb muscles and delayed the onset of clinical disease. However, this combinatory gene therapy did not produce a synergic effect compared with single therapies, suggesting an overlap between NRG1-I and NRG1-III activated pathways and their beneficial effects.

scholarly journals DNGR-1 limits Flt3L-mediated antitumor immunity by restraining tumor-infiltrating type I conventional dendritic cells

2021 ◽  
Vol 9 (5) ◽  
pp. e002054
Author(s):  
Francisco J Cueto ◽  
Carlos del Fresno ◽  
Paola Brandi ◽  
Alexis J. Combes ◽  
Elena Hernández-García ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Dendritic Cells ◽  
Tumor Growth ◽  
Antitumor Immunity ◽  
Elevated Serum ◽  
Dead Cell ◽  
Type I ◽  
Cross Presentation ◽  
Patients With Cancer ◽  
Deficient Mice

BackgroundConventional type 1 dendritic cells (cDC1s) are central to antitumor immunity and their presence in the tumor microenvironment associates with improved outcomes in patients with cancer. DNGR-1 (CLEC9A) is a dead cell-sensing receptor highly restricted to cDC1s. DNGR-1 has been involved in both cross-presentation of dead cell-associated antigens and processes of disease tolerance, but its role in antitumor immunity has not been clarified yet.MethodsB16 and MC38 tumor cell lines were inoculated subcutaneously into wild-type (WT) and DNGR-1-deficient mice. To overexpress Flt3L systemically, we performed gene therapy through the hydrodynamic injection of an Flt3L-encoding plasmid. To characterize the immune response, we performed flow cytometry and RNA-Seq of tumor-infiltrating cDC1s.ResultsHere, we found that cross-presentation of tumor antigens in the steady state was DNGR-1-independent. However, on Flt3L systemic overexpression, tumor growth was delayed in DNGR-1-deficient mice compared with WT mice. Of note, this protection was recapitulated by anti-DNGR-1-blocking antibodies in mice following Flt3L gene therapy. This improved antitumor immunity was associated with Batf3-dependent enhanced accumulation of CD8+ T cells and cDC1s within tumors. Mechanistically, the deficiency in DNGR-1 boosted an Flt3L-induced specific inflammatory gene signature in cDC1s, including Ccl5 expression. Indeed, the increased infiltration of cDC1s within tumors and their protective effect rely on CCL5/CCR5 chemoattraction. Moreover, FLT3LG and CCL5 or CCR5 gene expression signatures correlate with an enhanced cDC1 signature and a favorable overall survival in patients with cancer. Notably, cyclophosphamide elevated serum Flt3L levels and, in combination with the absence of DNGR-1, synergized against tumor growth.ConclusionDNGR-1 limits the accumulation of tumor-infiltrating cDC1s promoted by Flt3L. Thus, DNGR-1 blockade may improve antitumor immunity in tumor therapy settings associated to high Flt3L expression.

scholarly journals Histochemical Characterisation and Gene Expression Analysis of Skeletal Muscles from Maremmana and Aubrac Steers Reared on Grazing and Feedlot Systems

Animals ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 656
Author(s):  
Giulia Foggi ◽  
Francesca Ciucci ◽  
Maria Conte ◽  
Laura Casarosa ◽  
Andrea Serra ◽  
...  
Keyword(s):  
Gene Expression ◽  
Physical Activity ◽  
Muscle Fibre ◽  
Skeletal Muscles ◽  
Gene Expression Analysis ◽  
Type I ◽  
Triceps Brachii ◽  
Gene Expressions ◽  
Muscle Properties ◽  
Voluntary Physical Activity

This study aimed to characterise the fibre composition of Triceps brachii (TB) and Semimembranosus (SM) muscles from 20 Maremmana (MA) and 20 Aubrac (AU) steers, and the effect of grazing activity in comparison with feedlot system. The histochemical method was performed with the m-ATPase method with an acid pre-incubation, thus allowing to distinguish type I, IIA, and IIB fibres. Additionally, on total RNA extracted from SM muscle, the expressions of atp1a1, mt-atp6, and capn1 genes were evaluated, in order to find potential associations with muscle fibre histochemical characteristics. In SM muscle, the MA steers had the greater frequency of oxidative fibres (type I and IIA) and the higher atp1a1 expression, in comparison to AU steers. Conversely, AU steers had a greater frequency of type IIB fibres, and the higher capn1 expression. A similar histochemical pattern was observed in TB muscle. The grazing activity was probably insufficient to determine differences both for fibre proportion and size, and gene expressions, except for mt-atp6 expression that was surprisingly highest in feedlot MA in comparison to other steers. These findings further the knowledge of muscle properties belonging to these breeds, and the effect of voluntary physical activity since few studies were available in this regard.

scholarly journals Neuregulin-1 promotes functional improvement by enhancing collateral sprouting in SOD1G93A ALS mice and after partial muscle denervation

2016 ◽  
Vol 95 ◽  
pp. 168-178 ◽  
Author(s):  
Renzo Mancuso ◽  
Anna Martínez-Muriana ◽  
Tatiana Leiva ◽  
David Gregorio ◽  
Lorena Ariza ◽  
...  
Keyword(s):  
Functional Improvement ◽  
Muscle Denervation ◽  
Neuregulin 1 ◽  
Collateral Sprouting

scholarly journals The ketogenic diet increases Neuregulin 1 expression via elevating histone acetylation and its anti-seizure effect requires ErbB4 kinase activity

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jin Wang ◽  
Jie Huang ◽  
Shan Yao ◽  
Jia-Hui Wu ◽  
Hui-Bin Li ◽  
...  
Keyword(s):  
Histone Acetylation ◽  
Ketogenic Diet ◽  
Chromatin Immunoprecipitation ◽  
Kinase Activity ◽  
Control Diet ◽  
Synaptic Activity ◽  
Therapeutic Interventions ◽  
Type I ◽  
Neuregulin 1

Abstract Background The ketogenic diet (KD)has been considered an effective treatment for epilepsy, whereas its underlying mechanisms remain obscure. We have previously reported that the KD feeding increased Neuregulin 1 (NRG1) expression in the hippocampus; disruption of NRG1 signaling by genetically deleting its receptor-ErbB4 abolished KD’s effects on inhibitory synaptic activity and seizures. However, it is still unclear about the mechanisms underlying the effect of KD on NRG1 expression and whether the effects of KD require ErbB4 kinase activity. Methods The effects of the KD on NRG1 expression were assessed via western blotting and real-time PCR. Acetylation level at the Nrg1 promoter locus was examined using the chromatin immunoprecipitation technique. Kainic acid (KA)-induced acute seizure model was utilized to examine the effects of KD and histone deacetylase inhibitor-TSA on seizures. Synaptic activities in the hippocampus were recorded with the technique of electrophysiology. The obligatory role of ErbB4 kinase activity in KD’s effects on seizures and inhibitory synaptic activity was evaluated by using ErbB kinase antagonist and transgenic mouse-T796G. Results We report that KD specifically increases Type I NRG1 expression in the hippocampus. Using the chromatin immunoprecipitation technique, we observe increased acetylated-histone occupancy at the Nrg1 promoter locus of KD-fed mice. Treatment of TSA dramatically elevates NRG1 expression and diminishes the difference between the effects of the control diet (CD) and KD. These data indicate that KD increases NRG1 expression via up-regulating histone acetylation. Moreover, both pharmacological and genetic inhibitions of ErbB4 kinase activity significantly block the KD’s effects on inhibitory synaptic activity and seizure, suggesting an essential role of ErbB4 kinase activity. Conclusion These results strengthen our understanding of the role of NRG1/ErbB4 signaling in KD and shed light on novel therapeutic interventions for epilepsy.

scholarly journals Liver-directed gene therapy corrects cardiovascular lesions in feline mucopolysaccharidosis type I

2014 ◽  
Vol 111 (41) ◽  
pp. 14894-14899 ◽  
Author(s):  
C. Hinderer ◽  
P. Bell ◽  
B. L. Gurda ◽  
Q. Wang ◽  
J.-P. Louboutin ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Type I ◽  
Mucopolysaccharidosis Type ◽  
Mucopolysaccharidosis Type I

Enhanced Myotoxicity and Involvement of both Type I and II Fibers in Monensin-Tiamulin Toxicosis in Pigs

1985 ◽  
Vol 22 (4) ◽  
pp. 409-414 ◽  
Author(s):  
T. Umemura ◽  
A. Kawaminami ◽  
M. Goryo ◽  
C. Itakura
Keyword(s):  
Skeletal Muscles ◽  
Type I ◽  
Left Auricle ◽  
Simultaneous Administration ◽  
Cardiac Muscles ◽  
Histochemical Examination

Simultaneous administration of monensin and tiamulin to pigs resulted in enhanced myotoxicity. Skeletal muscles of tongue, diaphragm and legs were preferentially affected, whereas the masseter, longissimus thoracis and cardiac muscles, including the left auricle, were spared. Histochemical examination revealed an involvement of both type I and II fibers of skeletal muscles.

scholarly journals A Locomotor Disorder Clinically Similar to Spastic Paresis in an Adult Friesian Bull

1980 ◽  
Vol 17 (3) ◽  
pp. 305-315 ◽  
Author(s):  
R. Bradley ◽  
W.V.S. Wueratne
Keyword(s):  
Skeletal Muscles ◽  
Hind Limb ◽  
Type I ◽  
Type Ii ◽  
Hind Limbs ◽  
Type Ii Cell ◽  
Spastic Paresis ◽  
Flexor Digitorum ◽  
I Cells ◽  
Severe Type

A 5-year-old Friesian stud bull developed a progressive locomotor disorder on return to stud after a period of rest. He had defects in conformation exacerbated by poor condition. The hind limbs were excessively straight. When he stood or moved, the Achilles tendons and their associated muscles were rigid. The disorder clinically resembled spastic paresis of calves. Necropsy showed a degenerative arthropathy in all hind limb joints below the hip. Lesions were also in tendons and skeletal muscles. The M. flexor digitorum superficialis had severe type II cell atrophy with many ring. lobulated and moth-eaten type I cells.

Exercise increases the plasma membrane content of the Na+ -K+ pump and its mRNA in rat skeletal muscles

1996 ◽  
Vol 80 (2) ◽  
pp. 699-705 ◽  
Author(s):  
T. Tsakiridis ◽  
P. P. Wong ◽  
Z. Liu ◽  
C. D. Rodgers ◽  
M. Vranic ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Plasma Membrane ◽  
Skeletal Muscles ◽  
Plasma Membranes ◽  
Acute Exercise ◽  
Treadmill Running ◽  
Type I ◽  
Mrna Levels ◽  
Subunit Mrna ◽  
White Type

Muscle fibers adapt to ionic challenges of exercise by increasing the plasma membrane Na+-K+ pump activity. Chronic exercise training has been shown to increase the total amount of Na+-K+ pumps present in skeletal muscle. However, the mechanism of adaptation of the Na+-K+ pump to an acute bout of exercise has not been determined, and it is not known whether it involves alterations in the content of plasma membrane pump subunits. Here we examine the effect of 1 h of treadmill running (20 m/min, 10% grade) on the subcellular distribution and expression of Na+-K+ pump subunits in rat skeletal muscles. Red type I and IIa (red-I/IIa) and white type IIa and IIb (white-IIa/IIb) hindlimb muscles from resting and exercised female Sprague-Dawley rats were removed for subcellular fractionation. By homogenization and gradient centrifugation, crude membranes and purified plasma membranes were isolated and subjected to gel electrophoresis and immunoblotting by using pump subunit-specific antibodies. Furthermore, mRNA was isolated from specific red type I (red-I) and white type IIb (white-IIb) muscles and subjected to Northern blotting by using subunit-specific probes. In both red-I/IIa and white-IIa/IIb muscles, exercise significantly raised the plasma membrane content of the alpha1-subunit of the pump by 64 +/- 24 and 55 +/- 22%, respectively (P < 0.05), and elevated the alpha2-polypeptide by 43 +/- 22 and 94 +/- 39%, respectively (P < 0.05). No significant effect of exercise could be detected on the amount of these subunits in an internal membrane fraction or in total membranes. In addition, exercise significantly increased the alpha1-subunit mRNA in red-I muscle (by 50 +/- 7%; P < 0.05) and the beta2-subunit mRNA in white-IIb muscles (by 64 +/- 19%; P < 0.01), but the alpha2- and beta1-mRNA levels were unaffected in this time period. We conclude that increased presence of alpha1- and alpha2-polypeptides at the plasma membrane and subsequent elevation of the alpha1- and beta2-subunit mRNAs may be mechanisms by which acute exercise regulates the Na+-K+ pump of skeletal muscle.

Sign in / Sign up

Export Citation Format

Share Document