scholarly journals In vivo RyR1 reduction in muscle triggers a core-like myopathy

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Laurent Pelletier ◽  
Anne Petiot ◽  
Julie Brocard ◽  
Benoit Giannesini ◽  
Diane Giovannini ◽  
...  
Keyword(s):  
Calcium Release ◽  
Central Core ◽  
Central Core Disease ◽  
Gene Encoding ◽  
Adult Age ◽  
Progressive Muscle Weakness ◽  
Abnormal Mitochondria ◽  
Muscle Calcium ◽  
Muscle Biopsies

Abstract Mutations in the RYR1 gene, encoding the skeletal muscle calcium channel RyR1, lead to congenital myopathies, through expression of a channel with abnormal permeability and/or in reduced amount, but the direct functional whole organism consequences of exclusive reduction in RyR1 amount have never been studied. We have developed and characterized a mouse model with inducible muscle specific RYR1 deletion. Tamoxifen-induced recombination in the RYR1 gene at adult age resulted in a progressive reduction in the protein amount reaching a stable level of 50% of the initial amount, and was associated with a progressive muscle weakness and atrophy. Measurement of calcium fluxes in isolated muscle fibers demonstrated a reduction in the amplitude of RyR1-related calcium release mirroring the reduction in the protein amount. Alterations in the muscle structure were observed, with fibers atrophy, abnormal mitochondria distribution and membrane remodeling. An increase in the expression level of many proteins was observed, as well as an inhibition of the autophagy process. This model demonstrates that RyR1 reduction is sufficient to recapitulate most features of Central Core Disease, and accordingly similar alterations were observed in muscle biopsies from Dusty Core Disease patients (a subtype of Central Core Disease), pointing to common pathophysiological mechanisms related to RyR1 reduction.

scholarly journals In vivo RyR1 reduction in muscle triggers a core-like myopathy

2020 ◽  
Author(s):  
Laurent Pelletier ◽  
Anne Petiot ◽  
Julie Brocard ◽  
Benoit Giannesini ◽  
Diane Giovannini ◽  
...  
Keyword(s):  
Central Core ◽  
Central Core Disease ◽  
Expression Level ◽  
Progressive Reduction ◽  
Congenital Myopathies ◽  
Progressive Muscle Weakness ◽  
Channel Expression ◽  
Abnormal Mitochondria ◽  
Muscle Biopsies

AbstractSome mutations in the RYR1 gene lead to congenital myopathies, through reduction in this calcium channel expression level, but the functional whole organism consequences of reduction in RyR1 amount have never been studied. We have developed and characterized a mouse model with inducible muscle specific RYR1 deletion. Recombination in the RYR1 gene resulted in a progressive reduction in the protein amount and was associated with a progressive muscle weakness and atrophy. Calcium fluxes in isolated muscle fibers were accordingly reduced. Alterations in the muscle structure were observed, with fibers atrophy, abnormal mitochondria distribution, membrane remodeling, associated with increase in the expression level of many proteins and inhibition of the autophagy process. This model demonstrates that RyR1 reduction is sufficient to recapitulate most features of Central Core Disease, and accordingly similar alterations were observed in muscle biopsies from Central Core Disease patients, pointing to common pathophysiological mechanisms related to RyR1 reduction.

Central core disease: Histochemical and ultrastructural study of muscle biopsies of father and daughter

1978 ◽  
Vol 218 (1) ◽  
pp. 55-62 ◽  
Author(s):  
L. Palmucci ◽  
D. Schiffer ◽  
G. Monga ◽  
F. Mollo ◽  
M. Marchi
Keyword(s):  
Ultrastructural Study ◽  
Central Core ◽  
Central Core Disease ◽  
Muscle Biopsies

Autosomal Dominant Canine Malignant Hyperthermia Is Caused by a Mutation in the Gene Encoding the Skeletal Muscle Calcium Release Channel (RYR1 )

2001 ◽  
Vol 95 (3) ◽  
pp. 716-725 ◽  
Author(s):  
Monica C. Roberts ◽  
James R. Mickelson ◽  
Edward E. Patterson ◽  
Thomas E. Nelson ◽  
P. Jane Armstrong ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Calcium Release ◽  
Autosomal Dominant ◽  
Calcium Release Channel ◽  
Gene Encoding ◽  
Release Channel ◽  
In Vitro Contracture Test ◽  
Mixed Breed ◽  
Muscle Calcium

Background Malignant hyperthermia (MH) is an inherited disorder of skeletal muscle characterized by hypercarbia, rhabdomyolysis, generalized skeletal muscle contracture, cardiac dysrhythmia, and renal failure, that develops on exposure to succinylcholine or volatile anesthetic agents. All swine and up to 50% of human MH events are thought to be associated with mutations in the calcium release channel of the sarcoplasmic reticulum, also known as the ryanodine receptor (RYR1). Events resembling MH have been reported in other species, but none have undergone genetic investigation to date. Methods To determine the molecular basis of canine MH, a breeding colony was established with a male, mixed-breed, MH-susceptible (MHS) dog that survived an in vivo halothane-succinylcholine challenge. He was mated to three unaffected females to produce four litters and back-crossed to an affected daughter to produce one litter. One of his MHS sons was mated to an unaffected female to produce an additional litter. Forty-seven dogs were phenotyped with an in vitro contracture test and diagnosed as MHS or MH normal based on the North American in vitro contracture test protocol. Nine microsatellite markers in the vicinity of RYR1 on canine chromosome 1 (CFA01) were tested for linkage to the MHS phenotype. Mutational analysis in two MHS and two MH-normal dogs was performed with direct sequencing of polymerase chain reaction products and of cloned fragments that represent frequently mutated human RYR1 regions. A restriction fragment length polymorphism was chosen to detect the candidate mutation in the pedigree at large. Results Pedigree inspection revealed that MHS in this colony is transmitted as an autosomal dominant trait. FH2294, the marker closest to RYR1, is linked to MHS at a theta = 0.03 with a LOD score of 9.24. A T1640C mutation gives rise to an alanine for valine substitution of amino acid 547 in the RYR1 protein, generating a maximum LOD score of 12.29 at theta = 0.00. All dogs diagnosed as MHS by in vitro contracture test were heterozygous for the mutation, and all MH-normal dogs were homozygous for the T1640 allele. Conclusions These results indicate that autosomal dominant canine MH is caused by a mutation in the gene encoding the skeletal muscle calcium release channel and that the MHS trait in this pedigree of mixed-breed dogs is in perfect cosegregation with the RYR1 V547A mutation.

scholarly journals Evaluation of the Core Formation Process in Congenital Neuromuscular Disease With Uniform Type 1 Fiber and Central Core Disease

2020 ◽  
Vol 79 (12) ◽  
pp. 1370-1375
Author(s):  
Masashi Ogasawara ◽  
Megumu Ogawa ◽  
Ikuya Nonaka ◽  
Shinichiro Hayashi ◽  
Satoru Noguchi ◽  
...  
Keyword(s):  
Neuromuscular Disease ◽  
Structural Changes ◽  
Central Core ◽  
Central Core Disease ◽  
The Core ◽  
Advanced Stages ◽  
Congenital Neuromuscular Disease ◽  
Muscle Biopsies ◽  
Core Myopathy

Abstract Typical central core disease (CCD) is characterized pathologically by the presence of a core and is accompanied by type 1 fiber uniformity. Congenital neuromuscular disease with uniform type 1 fiber (CNMDU1) is characterized pathologically by the presence of type 1 fiber uniformity but without the abnormal structural changes in muscle fibers. Interestingly, typical CCD and 40% of CNMDU1 cases are caused by the same mutations in RYR1, and thus CNMDU1 has been considered an early precursor to CCD. To better understand the nature of CNMDU1, we re-evaluated muscle biopsies from 16 patients with CNMDU1 using immunohistochemistry to RYR1, triadin and TOM20, and compared this to muscle biopsies from 36 typical CCD patients. In CCD, RYR1, and triadin were present in the core regions, while TOM20 was absent in the core regions. Interestingly, in 5 CNMDU1 cases with the RYR1 mutation, RYR1, and triadin were similarly present in core-like areas, while TOM20 was absent in the subsarcolemmal region. Furthermore, there was a correlation between the core position and the disease duration or progression—the older patients in more advanced stages had more centralized cores. Our results indicate that CNMDU1 due to RYR1 mutation is a de facto core myopathy.

scholarly journals Early Osteoporosis in RYR1-Related Central Core Disease

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A191-A191
Author(s):  
Ezza Tariq ◽  
Lubna Mirza
Keyword(s):  
Motor Development ◽  
Calcium Release ◽  
Central Core ◽  
Central Core Disease ◽  
Heterozygous Mutation ◽  
Calcium Release Channel ◽  
Rare Presentation ◽  
T Score ◽  
First Case ◽  
Wide Range

Abstract Background: Central core disease(CDC) is a congenital neuromuscular myopathy with a wide range of phenotypic presentations, ranging from delayed motor development, frequent falls, and difficulty maintaining posture. CDC is a rare presentation of RYR1 (Calcium release channel gene) mutation, which is also linked with the etiology of malignant hyperthermia. Clinical Case: We present a case of a 57-year-old woman who was diagnosed with osteoporosis at age of 52 with a T score of -2.3 after she had a fragility fracture of the knee. She suffered from multiple falls from poor balance. Her most recent DXA bone density scan from December of 2018 showed a T score of -2.6. On genetic testing, she was found to have a RYR1 heterozygous mutation, on exon 28.c.3800C to G(p.P1267 Arg). This sequence change led to the replacement of proline with arginine at codon 1267 of RyR1 protein. None of her immediate and extended family members showed any signs of CDC. We assume that the loss of sufficient muscle strain on bone and the catabolic effect of RYR1 myopathy are major causes of osteoporosis in our patient, although menopause, personal history of smoking, and alcohol intake could also be contributing factors. Teriparatide along with daily Calcium and Vitamin-D was prescribed. Later on, denosumab injection was also added to the regimen. The patient still has at least one episode of unprovoked fall in a month, but luckily she has not had any more fractures. Conclusion: To our knowledge, this is the first case where early osteoporosis in RYR1 myopathy has been reported.

scholarly journals The Multifaceted Roles of MicroRNAs in Cystic Fibrosis

Diagnostics ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1102
Author(s):  
Fatima Domenica Elisa De Palma ◽  
Valeria Raia ◽  
Guido Kroemer ◽  
Maria Chiara Maiuri
Keyword(s):  
Cystic Fibrosis ◽  
Respiratory Infections ◽  
Current Knowledge ◽  
Pancreatic Insufficiency ◽  
Clinical Manifestations ◽  
Predictive Biomarkers ◽  
Loss Of Function ◽  
Gene Encoding ◽  
Multisystemic Disease

Cystic fibrosis (CF) is a lifelong disorder affecting 1 in 3500 live births worldwide. It is a monogenetic autosomal recessive disease caused by loss-of-function mutations in the gene encoding the chloride channel cystic fibrosis transmembrane conductance regulator (CFTR), the impairment of which leads to ionic disequilibria in exocrine organs. This translates into a chronic multisystemic disease characterized by airway obstruction, respiratory infections, and pancreatic insufficiency as well as hepatobiliary and gastrointestinal dysfunction. Molecular characterization of the mutational heterogeneity of CFTR (affected by more than 2000 variants) improved the understanding and management of CF. However, these CFTR variants are linked to different clinical manifestations and phenotypes, and they affect response to treatments. Expanding evidence suggests that multisystemic disease affects CF pathology via impairing either CFTR or proteins regulated by CFTR. Thus, altering the expression of miRNAs in vivo could constitute an appealing strategy for developing new CF therapies. In this review, we will first describe the pathophysiology and clinical management of CF. Then, we will summarize the current knowledge on altered miRNAs in CF patients, with a focus on the miRNAs involved in the deregulation of CFTR and in the modulation of inflammation. We will highlight recent findings on the potential utility of measuring circulating miRNAs in CF as diagnostic, prognostic, and predictive biomarkers. Finally, we will provide an overview on potential miRNA-based therapeutic approaches.

SPT15, the gene encoding the yeast TATA binding factor TFIID, is required for normal transcription initiation in vivo

Cell ◽  
1989 ◽  
Vol 58 (6) ◽  
pp. 1183-1191 ◽  
Author(s):  
David M. Eisenmann ◽  
Catherine Dollard ◽  
Fred Winston
Keyword(s):  
Transcription Initiation ◽  
Gene Encoding ◽  
Binding Factor

scholarly journals Genetic deletion of trkB.T1 increases neuromuscular function

2012 ◽  
Vol 302 (1) ◽  
pp. C141-C153 ◽  
Author(s):  
Susan G. Dorsey ◽  
Richard M. Lovering ◽  
Cynthia L. Renn ◽  
Carmen C. Leitch ◽  
Xinyue Liu ◽  
...  
Keyword(s):  
Calcium Release ◽  
Contractile Activity ◽  
Muscle Tension ◽  
Neuromuscular Synapse ◽  
Neuromuscular Function ◽  
In Vitro Assays ◽  
Tyrosine Kinase Receptor ◽  
Akt Activation

Neurotrophin-dependent activation of the tyrosine kinase receptor trkB.FL modulates neuromuscular synapse maintenance and function; however, it is unclear what role the alternative splice variant, truncated trkB ( trkB.T1), may have in the peripheral neuromuscular axis. We examined this question in trkB.T1 null mice and demonstrate that in vivo neuromuscular performance and nerve-evoked muscle tension are significantly increased. In vitro assays indicated that the gain-in-function in trkB.T1 −/− animals resulted specifically from an increased muscle contractility, and increased electrically evoked calcium release. In the trkB.T1 null muscle, we identified an increase in Akt activation in resting muscle as well as a significant increase in trkB.FL and Akt activation in response to contractile activity. On the basis of these findings, we conclude that the trkB signaling pathway might represent a novel target for intervention across diseases characterized by deficits in neuromuscular function.

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