scholarly journals Pore mutation N617D in the skeletal muscle DHPR blocks Ca2+ influx due to atypical high-affinity Ca2+ binding

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Anamika Dayal ◽  
Monica L Fernández-Quintero ◽  
Klaus R Liedl ◽  
Manfred Grabner
Keyword(s):  
Skeletal Muscle ◽  
Molecular Model ◽  
Ion Selectivity ◽  
Genetically Engineered ◽  
Developmental Pathways ◽  
Monovalent Cations ◽  
Pore Region ◽  
Genetically Engineered Mouse Models ◽  
High Affinity ◽  
Ec Coupling

Skeletal muscle excitation-contraction (EC) coupling roots in Ca2+-influx-independent inter-channel signaling between the sarcolemmal dihydropyridine receptor (DHPR) and the ryanodine receptor (RyR1) in the sarcoplasmic reticulum. Although DHPR Ca2+ influx is irrelevant for EC coupling, its putative role in other muscle-physiological and developmental pathways was recently examined using two distinct genetically engineered mouse models carrying Ca2+ non-conducting DHPRs: DHPR(N617D) (Dayal et al., 2017) and DHPR(E1014K) (Lee et al., 2015). Surprisingly, despite complete block of DHPR Ca2+-conductance, histological, biochemical, and physiological results obtained from these two models were contradictory. Here we characterize the permeability and selectivity properties and henceforth the mechanism of Ca2+ non-conductance of DHPR(N617). Our results reveal that only mutant DHPR(N617D) with atypical high-affinity Ca2+ pore-binding is tight for physiologically relevant monovalent cations like Na+ and K+. Consequently, we propose a molecular model of cooperativity between two ion selectivity rings formed by negatively charged residues in the DHPR pore region.

scholarly journals Two Types of Mouse Models for Sarcopenia Research: Senescence Acceleration and Genetic Modification Models

2021 ◽  
Vol 28 (3) ◽  
pp. 179-192
Author(s):  
Kyung-Wan Baek ◽  
Youn-Kwan Jung ◽  
Jin Sung Park ◽  
Ji-Seok Kim ◽  
Young-Sool Hah ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mouse Models ◽  
International Classification Of Diseases ◽  
Genetically Engineered ◽  
Hindlimb Unloading ◽  
Muscle Properties ◽  
Genetically Engineered Mouse Models ◽  
Classification Of Diseases ◽  
Senescence Accelerated Mouse

Sarcopenia leads to loss of skeletal muscle mass, quality, and strength due to aging; it was recently given a disease code (International Classification of Diseases, Tenth Revision, Clinical Modification, M62.84). As a result, in recent years, sarcopenia-related research has increased. In addition, various studies seeking to prevent and treat sarcopenia by identifying the various mechanisms related to the reduction of skeletal muscle properties have been conducted. Previous studies have identified muscle synthesis and breakdown; investigating them has generated evidence for preventing and treating sarcopenia. Mouse models are still the most useful ones for determining mechanisms underlying sarcopenia through correlations and interventions involving specific genes and their phenotypes. Mouse models used to study sarcopenia often induce muscle atrophy by hindlimb unloading, denervation, or immobilization. Though it is less frequently used, the senescence-accelerated mouse can also be useful for sarcopenia research. Herein, we discuss cases where senescence-accelerated and genetically engineered mouse models were used in sarcopenia research and different perspectives to use them.

Olfactomedin-like 2A, 2B and 3 are differentially expressed in breast cancer metastases.

2019 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Genetically Engineered ◽  
Differentially Expressed ◽  
Genetically Engineered Mouse Models ◽  
Breast Cancer Metastases ◽  
Multiple Datasets ◽  
Cancer Metastases ◽  
Distant Organ ◽  
Metastatic Process ◽  
Differential Gene

Differential gene expression analysis of multiple datasets, in mice and in men revealed that transcripts of the olfactomedin-like family are differentially expressed in metastases, both in patients with breast cancer and in genetically engineered mouse models of breast cancer. The expression of olfactomedin-like genes was perturbed in metastases to the bone, brain and the lung, suggesting that these molecules function in the metastatic process rather than having tissue-specific associations with the site of dissemination. The olfactomedin-like family may play a role in the progression of breast cancer from frank tumor to colonization of distant organ sites.

scholarly journals DIPG-41. DISSECTING THE MECHANISTIC BASIS FOR ACVR1 AND PIK3CA MUTATION CO-OCCURRENCE IN DIFFUSE MIDLINE GLIOMAS USING GENETICALLY ENGINEERED MOUSE MODELS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii295-iii295
Author(s):  
Annette Wu ◽  
Tak Mak ◽  
Jerome Fortin
Keyword(s):  
Mouse Models ◽  
Pik3ca Mutation ◽  
Cell Lineage ◽  
Gene Expression Signature ◽  
Genetically Engineered ◽  
Genetically Engineered Mouse Models ◽  
Dismal Prognosis ◽  
Human Pathology ◽  
Genes Encoding ◽  
Mechanistic Basis

Abstract Diffuse midline gliomas (DMGs) are aggressive childhood brain tumors with a dismal prognosis. Most of these tumors carry K27M mutations in histone H3-encoding genes, particularly H3F3A and HIST1H3B. In addition, activating mutations in ACVR1 and PIK3CA co-occur in a subset of DMGs. To understand how these lesions drive the development of DMGs, we generated genetically engineered mouse models in which Acvr1G328V, Hist1h3bK27M, and Pik3caH1047R are targeted to the OLIG2-expressing cell lineage. Animals carrying Acvr1G328V and Pik3caH1047R, with (“AHPO”) or without (“APO”) Hist1h3bK27M, developed high-grade diffuse gliomas involving midline and forebrain regions. Neither Acvr1G328V nor Pik3caH1047R drove tumorigenesis by themselves, but Acvr1G328V was sufficient to cause oligodendroglial differentiation arrest, pointing to a role in the earliest stages of gliomas formation. Transcriptomic analyses of AHPO and APO tumors indicated a predominantly proneural and oligodendrocyte precursor-like gene expression signature, consistent with the corresponding human pathology. Genes encoding transcription factors (TFs) with dual roles in controlling glial and neuronal differentiation were upregulated in tumors. Some of these genes were mildly induced by Acvr1G328V alone. Functional experiments using CRISPR/Cas9-mediated gene editing in patient-derived cell lines confirmed a role for some of these TFs in controlling DMG cell fitness. Overall, our results suggest that Pik3caH1047R consolidates Acvr1G328V-induced glial differentiation arrest to drive DMG development and progression.

Effect of training on insulin binding to rat skeletal muscle sarcolemmal vesicles

1986 ◽  
Vol 250 (5) ◽  
pp. E570-E575
Author(s):  
G. K. Grimditch ◽  
R. J. Barnard ◽  
S. A. Kaplan ◽  
E. Sternlicht
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Exercise Training ◽  
Insulin Binding ◽  
Whole Body ◽  
Rat Skeletal Muscle ◽  
Binding Studies ◽  
Muscle Enzyme ◽  
Intravenous Glucose ◽  
High Affinity

We examined the hypothesis that the exercise training-induced increase in skeletal muscle insulin sensitivity is mediated by adaptations in insulin binding to sarcolemmal (SL) insulin receptors. Insulin binding studies were performed on rat skeletal muscle SL isolated from control and trained rats. No significant differences were noted between groups in body weight or fat. An intravenous glucose tolerance test showed an increase in whole-body insulin sensitivity with training, and specific D-glucose transport studies on isolated SL vesicles indicated that this was due in part to adaptations in skeletal muscle. Enzyme marker analyses revealed no differences in yield, purity, or contamination of SL membranes between the two groups. Scatchard analyses indicated no significant differences in the number of insulin binding sites per milligram SL protein on the high-affinity (15.0 +/- 4.1 vs. 18.1 +/- 6.4 X 10(9)) or on the low-affinity portions (925 +/- 80 vs. 884 +/- 106 X 10(9)) of the curves. The association constants of the high-affinity (0.764 +/- 0.154 vs. 0.685 +/- 0.264 X 10(9) M-1) and of the low affinity sites (0.0096 +/- 0.0012 vs. 0.0102 +/- 0.0012 X 10(9) M-1) also were similar. These results do not support the hypothesis that the increased sensitivity to insulin after exercise training is due to changes in SL insulin receptor binding.

scholarly journals Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma

2016 ◽  
Vol 113 (42) ◽  
pp. E6409-E6417 ◽  
Author(s):  
David G. McFadden ◽  
Katerina Politi ◽  
Arjun Bhutkar ◽  
Frances K. Chen ◽  
Xiaoling Song ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Mouse Models ◽  
Cancer Progression ◽  
Large Scale ◽  
Human Cancer ◽  
Genetically Engineered ◽  
Model Systems ◽  
Driver Mutations ◽  
Genetic Profile ◽  
Genetically Engineered Mouse Models

Genetically engineered mouse models (GEMMs) of cancer are increasingly being used to assess putative driver mutations identified by large-scale sequencing of human cancer genomes. To accurately interpret experiments that introduce additional mutations, an understanding of the somatic genetic profile and evolution of GEMM tumors is necessary. Here, we performed whole-exome sequencing of tumors from three GEMMs of lung adenocarcinoma driven by mutant epidermal growth factor receptor (EGFR), mutant Kirsten rat sarcoma viral oncogene homolog (Kras), or overexpression of MYC proto-oncogene. Tumors from EGFR- and Kras-driven models exhibited, respectively, 0.02 and 0.07 nonsynonymous mutations per megabase, a dramatically lower average mutational frequency than observed in human lung adenocarcinomas. Tumors from models driven by strong cancer drivers (mutant EGFR and Kras) harbored few mutations in known cancer genes, whereas tumors driven by MYC, a weaker initiating oncogene in the murine lung, acquired recurrent clonal oncogenic Kras mutations. In addition, although EGFR- and Kras-driven models both exhibited recurrent whole-chromosome DNA copy number alterations, the specific chromosomes altered by gain or loss were different in each model. These data demonstrate that GEMM tumors exhibit relatively simple somatic genotypes compared with human cancers of a similar type, making these autochthonous model systems useful for additive engineering approaches to assess the potential of novel mutations on tumorigenesis, cancer progression, and drug sensitivity.

Genetically Engineered Mouse Models of Esophageal Cancer

2021 ◽  
pp. 112757
Author(s):  
Reihaneh Alsadat Mahmoudian ◽  
Moein Farshchian ◽  
Mohammad Reza Abbaszadegan
Keyword(s):  
Esophageal Cancer ◽  
Mouse Models ◽  
Genetically Engineered ◽  
Genetically Engineered Mouse Models
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