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Domellöf, Fatima Pedrosa
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Dennhag, N., Kahsay, A., Nissen, I., Nord, H., Chermenina, M., Liu, J., . . . Domellöf, F. P. (2024). fhl2b mediates extraocular muscle protection in zebrafish models of muscular dystrophies and its ectopic expression ameliorates affected body muscles. Nature Communications, 15(1), Article ID 1950.
Öppna denna publikation i ny flik eller fönster >>fhl2b mediates extraocular muscle protection in zebrafish models of muscular dystrophies and its ectopic expression ameliorates affected body muscles
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2024 (Engelska)Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 15, nr 1, artikel-id 1950Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

In muscular dystrophies, muscle fibers loose integrity and die, causing significant suffering and premature death. Strikingly, the extraocular muscles (EOMs) are spared, functioning well despite the disease progression. Although EOMs have been shown to differ from body musculature, the mechanisms underlying this inherent resistance to muscle dystrophies remain unknown. Here, we demonstrate important differences in gene expression as a response to muscle dystrophies between the EOMs and trunk muscles in zebrafish via transcriptomic profiling. We show that the LIM-protein Fhl2 is increased in response to the knockout of desmin, plectin and obscurin, cytoskeletal proteins whose knockout causes different muscle dystrophies, and contributes to disease protection of the EOMs. Moreover, we show that ectopic expression of fhl2b can partially rescue the muscle phenotype in the zebrafish Duchenne muscular dystrophy model sapje, significantly improving their survival. Therefore, Fhl2 is a protective agent and a candidate target gene for therapy of muscular dystrophies.

Ort, förlag, år, upplaga, sidor
Springer Nature, 2024
Nationell ämneskategori
Cell- och molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-222359 (URN)10.1038/s41467-024-46187-x (DOI)38431640 (PubMedID)2-s2.0-85186557555 (Scopus ID)
Tillgänglig från: 2024-03-15 Skapad: 2024-03-15 Senast uppdaterad: 2024-03-15Bibliografiskt granskad
Kahsay, A., Dennhag, N., Liu, J.-X., Nord, H., Rönnbäck, H., Thorell, A. E., . . . Domellöf, F. P. (2024). Obscurin maintains myofiber identity in extraocular muscles. Investigative Ophthalmology and Visual Science, 65(2), Article ID 19.
Öppna denna publikation i ny flik eller fönster >>Obscurin maintains myofiber identity in extraocular muscles
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2024 (Engelska)Ingår i: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 65, nr 2, artikel-id 19Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Purpose: The cytoskeleton of the extraocular muscles (EOMs) is significantly different from that of other muscles. We aimed to investigate the role of obscurin, a fundamental cytoskeletal protein, in the EOMs.

Methods: The distribution of obscurin in human and zebrafish EOMs was compared using immunohistochemistry. The two obscurin genes in zebrafish, obscna and obscnb, were knocked out using CRISPR/Cas9, and the EOMs were investigated using immunohistochemistry, qPCR, and in situ hybridization. The optokinetic reflex (OKR) in five-day-old larvae and adult obscna−/−;obscnb−/− and sibling control zebrafish was analyzed. Swimming distance was recorded at the same age.

Results: The obscurin distribution pattern was similar in human and zebrafish EOMs. The proportion of slow and fast myofibers was reduced in obscna−/−;obscnb−/− zebrafish EOMs but not in trunk muscle, whereas the number of myofibers containing cardiac myosin myh7 was significantly increased in EOMs of obscurin double mutants. Loss of obscurin resulted in less OKRs in zebrafish larvae but not in adult zebrafish.

Conclusions: Obscurin expression is conserved in normal human and zebrafish EOMs. Loss of obscurin induces a myofiber type shift in the EOMs, with upregulation of cardiac myosin heavy chain, myh7, showing an adaptation strategy in EOMs. Our model will facilitate further studies in conditions related to obscurin.

Ort, förlag, år, upplaga, sidor
Association for Research in Vision and Ophthalmology, 2024
Nyckelord
extraocular muscles, myofiber, myosin heavy chain 7, obscurin, zebrafish
Nationell ämneskategori
Oftalmologi
Identifikatorer
urn:nbn:se:umu:diva-218165 (URN)10.1167/iovs.65.2.19 (DOI)38334702 (PubMedID)2-s2.0-85184789466 (Scopus ID)
Forskningsfinansiär
Vetenskapsrådet, 2018-02401Umeå universitetRegion VästerbottenUmeå universitet, FS 2.1.6-1911-22Stiftelsen Kronprinsessan Margaretas arbetsnämnd för synskadade
Anmärkning

Originally included in thesis in manuscript form. 

Tillgänglig från: 2023-12-18 Skapad: 2023-12-18 Senast uppdaterad: 2024-03-05Bibliografiskt granskad
Vicente, A., Sloniecka, M., Liu, J.-X., Byström, B. & Domellöf, F. P. (2022). Aniridia-related keratopathy relevant cell signaling pathways in human fetal corneas. Histochemistry and Cell Biology, 158(2), 169-180
Öppna denna publikation i ny flik eller fönster >>Aniridia-related keratopathy relevant cell signaling pathways in human fetal corneas
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2022 (Engelska)Ingår i: Histochemistry and Cell Biology, ISSN 0948-6143, E-ISSN 1432-119X, Vol. 158, nr 2, s. 169-180Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

We aimed to study aniridia-related keratopathy (ARK) relevant cell signaling pathways [Notch1, Wnt/β-catenin, Sonic hedgehog (SHH) and mTOR] in normal human fetal corneas compared with normal human adult corneas and ARK corneas. We found that fetal corneas at 20 weeks of gestation (wg) and normal adult corneas showed similar staining patterns for Notch1; however 10–11 wg fetal corneas showed increased presence of Notch1. Numb and Dlk1 had an enhanced presence in the fetal corneas compared with the adult corneas. Fetal corneas showed stronger immunolabeling with antibodies against β-catenin, Wnt5a, Wnt7a, Gli1, Hes1, p-rpS6, and mTOR when compared with the adult corneas. Gene expression of Notch1, Wnt5A, Wnt7A, β-catenin, Hes1, mTOR, and rps6 was higher in the 9–12 wg fetal corneas compared with adult corneas. The cell signaling pathway differences found between human fetal and adult corneas were similar to those previously found in ARK corneas with the exception of Notch1. Analogous profiles of cell signaling pathway activation between human fetal corneas and ARK corneas suggests that there is a less differentiated host milieu in ARK.

Ort, förlag, år, upplaga, sidor
Springer, 2022
Nyckelord
Aniridia, Fetal cornea, Adult cornea, Sonic hedgehog, Notch, mTOR, Wnt
Nationell ämneskategori
Oftalmologi
Identifikatorer
urn:nbn:se:umu:diva-164256 (URN)10.1007/s00418-022-02099-9 (DOI)000799082100002 ()35551459 (PubMedID)2-s2.0-85129792626 (Scopus ID)
Forskningsfinansiär
Region VästerbottenUmeå universitetStiftelsen Kronprinsessan Margaretas arbetsnämnd för synskadadeÅke Wibergs Stiftelse
Anmärkning

Originally included in thesis in manuscript form.

Tillgänglig från: 2019-10-18 Skapad: 2019-10-18 Senast uppdaterad: 2023-09-05Bibliografiskt granskad
Nord, H., Kahsay, A., Dennhag, N., Domellöf, F. P. & von Hofsten, J. (2022). Genetic compensation between Pax3 and Pax7 in zebrafish appendicular muscle formation. Developmental Dynamics, 251(9), 1423-1438
Öppna denna publikation i ny flik eller fönster >>Genetic compensation between Pax3 and Pax7 in zebrafish appendicular muscle formation
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2022 (Engelska)Ingår i: Developmental Dynamics, ISSN 1058-8388, E-ISSN 1097-0177, Vol. 251, nr 9, s. 1423-1438Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Background: Migrating muscle progenitors delaminate from the somite and subsequently form muscle tissue in distant anatomical regions such as the paired appendages, or limbs. In amniotes, this process requires a signaling cascade including the transcription factor paired box 3 (Pax3).

Results: In this study, we found that, unlike in mammals, pax3a/3b double mutant zebrafish develop near to normal appendicular muscle. By analyzing numerous mutant combinations of pax3a, pax3b and pax7a, and pax7b, we determined that there is a feedback system and a compensatory mechanism between Pax3 and Pax7 in this developmental process, even though Pax7 alone is not required for appendicular myogenesis. pax3a/3b/7a/7b quadruple mutant developed muscle-less pectoral fins.

Conclusions: We found that Pax3 and Pax7 are redundantly required during appendicular myogenesis in zebrafish, where Pax7 is able to activate the same developmental programs as Pax3 in the premigratory progenitor cells.

Ort, förlag, år, upplaga, sidor
John Wiley & Sons, 2022
Nyckelord
appendicular myogenesis, limb development, muscle regeneration
Nationell ämneskategori
Cell- och molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-187293 (URN)10.1002/dvdy.415 (DOI)000691719300001 ()34435397 (PubMedID)2-s2.0-85113911054 (Scopus ID)
Forskningsfinansiär
CancerfondenUmeå universitet
Anmärkning

Special Issue

Tillgänglig från: 2021-09-07 Skapad: 2021-09-07 Senast uppdaterad: 2023-12-18Bibliografiskt granskad
Liu, J.-X. & Domellöf, F. P. (2021). Cytoskeletal Proteins in Myotendinous Junctions of Human Extraocular Muscles. Investigative Ophthalmology and Visual Science, 62(2), 1-10
Öppna denna publikation i ny flik eller fönster >>Cytoskeletal Proteins in Myotendinous Junctions of Human Extraocular Muscles
2021 (Engelska)Ingår i: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 62, nr 2, s. 1-10Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Purpose: The purpose of this study was to investigate the cytoskeletal composition of myotendinous junctions (MTJs) in the human extraocular muscles (EOMs). Desmin and other major cytoskeletal proteins are enriched at the MTJs of ordinary myofibers, where they are proposed to be of particular importance for force transmission and required to maintain myofiber integrity. Methods: EOM and limb muscle samples were analyzed with immunohistochemistry using antibodies against the intermediate filament proteins desmin, nestin, keratin 19, vimentin, and different myosin heavy chain (MyHC) isoforms. MTJs were identified by labeling with antibodies against laminin or tenascin. Results: In contrast to MTJs in lumbrical muscle where desmin, nestin, and keratin 19 were always present, approximately one-third of the MTJs in the EOMs lacked either desmin and/or nestin, and all MTJs lacked keratin 19. Approximately 6% of the MTJs in the EOMs lacked all of these key cytoskeletal proteins. Conclusions: The cytoskeletal protein composition of MTJs in human EOMs differed significantly from that of MTJs in limb muscles. These differences in cytoskeletal protein composition may indicate particular adaptation to meet the functional requirements of the EOMs.

Ort, förlag, år, upplaga, sidor
ARVO journals, 2021
Nationell ämneskategori
Oftalmologi
Identifikatorer
urn:nbn:se:umu:diva-181570 (URN)10.1167/iovs.62.2.19 (DOI)000624567800019 ()2-s2.0-85101667975 (Scopus ID)
Tillgänglig från: 2021-03-19 Skapad: 2021-03-19 Senast uppdaterad: 2023-09-05Bibliografiskt granskad
Dennhag, N., Liu, J.-X., Nord, H., von Hofsten, J. & Domellöf, F. P. (2020). Absence of Desmin in Myofibers of the Zebrafish Extraocular Muscles. Translational Vision Science & Technology, 9(10), Article ID 1.
Öppna denna publikation i ny flik eller fönster >>Absence of Desmin in Myofibers of the Zebrafish Extraocular Muscles
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2020 (Engelska)Ingår i: Translational Vision Science & Technology, E-ISSN 2164-2591, Vol. 9, nr 10, artikel-id 1Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Purpose: To study the medial rectus (MR) muscle of zebrafish (Danio rerio) with respect to the pattern of distribution of desmin and its correlation to distinct types of myofibers and motor endplates.

Methods: The MRs of zebrafish were examined using confocal microscopy in whole-mount longitudinal specimens and in cross sections processed for immunohistochemistry with antibodies against desmin, myosin heavy chain isoforms, and innervation markers. Desmin patterns were correlated to major myofiber type and type of innervation. A total of 1382 myofibers in nine MR muscles were analyzed.

Results: Four distinct desmin immunolabeling patterns were found in the zebrafish MRs. Approximately a third of all slow myofibers lacked desmin, representing 8.5% of the total myofiber population. The adult zebrafish MR muscle displayed en grappe, en plaque, and multiterminal en plaque neuromuscular junctions (NMJs) with intricate patterns of desmin immunolabeling.

Conclusions: The MRs of zebrafish showed important similarities with the human extraocular muscles with regard to the pattern of desmin distribution and presence of the major types of NMJs and can be regarded as an adequate model to further study the role of desmin and the implications of heterogeneity in cytoskeletal protein composition.

Translational Relevance: The establishment of a zebrafish model to study the cytoskeleton in muscles that are particularly resistant to muscle disease opens new avenues to understand human myopathies and muscle dystrophies and may provide clues to new therapies.

Ort, förlag, år, upplaga, sidor
Association for Research in Vision and Ophthalmology, 2020
Nyckelord
extraocular muscles, desmin, neuromuscular junction, myosin heavy chain, zebrafish, multiterminal en plaque endplates
Nationell ämneskategori
Oftalmologi
Identifikatorer
urn:nbn:se:umu:diva-177160 (URN)10.1167/tvst.9.10.1 (DOI)000587388500001 ()32953241 (PubMedID)2-s2.0-85093896190 (Scopus ID)
Tillgänglig från: 2020-12-08 Skapad: 2020-12-08 Senast uppdaterad: 2023-12-18Bibliografiskt granskad
Liu, J.-X. & Domellöf, F. P. (2020). Complex Correlations Between Desmin Content, Myofiber Types, and Innervation Patterns in the Human Extraocular Muscles. Investigative Ophthalmology and Visual Science, 61(3), Article ID 15.
Öppna denna publikation i ny flik eller fönster >>Complex Correlations Between Desmin Content, Myofiber Types, and Innervation Patterns in the Human Extraocular Muscles
2020 (Engelska)Ingår i: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 61, nr 3, artikel-id 15Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

PURPOSE. To investigate whether the distribution of intermediate filament protein desmin is related to the different patterns of innervation in the human extraocular muscles (EOMs).

METHODS. EOM samples were analyzed with immunohistochemistry using antibodies against desmin, vimentin, different myosin heavy chain (MyHC) isoforms, and fetal and adult acetylcholine receptor (AChR) subunits. Neuromuscular junctions (NMJs) were identified with alpha-bungarotoxin or with antibodies against neurofilament and synaptophysin.

RESULTS. Desmin was present in the vast majority of myofibers, but it was weakly present or absent in a limited area in the close vicinity of the single en plaque NMJs in less than half of these myofibers. Desmin was either present or lacking in MyHCsto/I myofibers displaying multiple en grappe endings but present in MyHCsto/I myofibers receiving spiral nerve endings. In MyHCeom myofibers displaying multiterminal en plaque endings, desmin was either present or absent irrespective of AChR subunits or EOM layer. Vimentin did not substitute for the lack of desmin.

CONCLUSIONS. The results indicate that the human EOMs have a more complex cytoskeletal organization than other muscles and suggest additional signalling mechanisms from the NMJs to the myofibers.

Ort, förlag, år, upplaga, sidor
The Association for Research in Vision and Ophthalmology, Inc. (ARVO), 2020
Nyckelord
extraocular muscles, desmin, intermediate filament, neuromuscular junctions, multiple en grappe endings, multiterminal en plaque endings, acetylcholine receptor subunit
Nationell ämneskategori
Oftalmologi
Identifikatorer
urn:nbn:se:umu:diva-170422 (URN)10.1167/iovs.61.3.15 (DOI)000524168000015 ()32176266 (PubMedID)2-s2.0-85081978982 (Scopus ID)
Tillgänglig från: 2020-05-05 Skapad: 2020-05-05 Senast uppdaterad: 2023-03-24Bibliografiskt granskad
Domellöf, F. P. & Liu, J.-X. (2020). The cytoskeleton of myotendinous junctions in human extraocular muscles. Paper presented at Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO), MAY 01-07, 2020, ELECTR NETWORK. Investigative Ophthalmology and Visual Science, 61(7)
Öppna denna publikation i ny flik eller fönster >>The cytoskeleton of myotendinous junctions in human extraocular muscles
2020 (Engelska)Ingår i: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 61, nr 7Artikel i tidskrift, Meeting abstract (Övrigt vetenskapligt) Published
Abstract [en]

Purpose: To systematically investigate the composition of the cytoskeleton of the myotendinous junctions (MTJs) in human extraocular muscles (EOMs).

Methods: Ten human EOM samples collected with ethical permission were processed for immunofluorescence with antibodies against the cytoskeletal proteins desmin, nestin, vimentin and cytokeratin 19; various myosin heavy chain (MyHC) isoforms as well as antibodies against tenascin or laminin to identify the MTJs.

Results: The majority of the MTJs in both orbital and global layer contained desmin but an important proportion of them did not show increased levels of immunostaining at the folds of the MTJ, in contrast to other muscles. Desmin was absent from approximately 15% of the MTJs and mostly in myofibers containing MyHCIIa. Nestin was present in approximately 91% of the MTJs. Four different combinations were encountered regarding immunolabeling for desmin+nestin at the MTJs, including absence of both in a subgroup of MTJs, irrespective of fiber type. Vimentin was not present at the MTJs and cytokeratin 19 was either present or absent from the MTJs.

Conclusions: The present data on the composition of the cytoskeleton at the MTJs in the EOMs raises fundamental questions regarding our previous knowledge on the role of these proteins for force transmission. We propose a novel model to further investigate these questions.

Ort, förlag, år, upplaga, sidor
The Association for Research in Vision and Ophthalmology (ARVO), 2020
Nationell ämneskategori
Oftalmologi
Identifikatorer
urn:nbn:se:umu:diva-174847 (URN)000554495702146 ()
Konferens
Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO), MAY 01-07, 2020, ELECTR NETWORK
Anmärkning

Meeting Abstract: 1141

Tillgänglig från: 2020-09-18 Skapad: 2020-09-18 Senast uppdaterad: 2020-09-18Bibliografiskt granskad
Liu, J.-X., Dennhag, N. & Domellöf, F. P. (2020). Understanding the extraocular muscles: Connective tissue, motor endplates and the cytoskeleton. The Biochemist, 42(5), 52-57
Öppna denna publikation i ny flik eller fönster >>Understanding the extraocular muscles: Connective tissue, motor endplates and the cytoskeleton
2020 (Engelska)Ingår i: The Biochemist, ISSN 0954-982X, Vol. 42, nr 5, s. 52-57Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

We constantly direct our eyes to the object of interest with the help of the extraocular muscles, andthereby use foveal fixation to attain the best possible visual acuity. The muscles around the eye arerather different from other skeletal muscles, being, for example, simultaneously the fastest musclesin the body and impossible to exhaust. The most exciting property of the extraocular muscles is theirunique response to disease, as they often remain unaffected in muscle conditions which lead tosevere handicap and premature death. Understanding the coping strategies that allow the extraocularmuscles to remain unaffected may provide clues for the future treatment of severe diseases such asmuscle dystrophies.

Ort, förlag, år, upplaga, sidor
Portland Press, 2020
Nationell ämneskategori
Oftalmologi
Identifikatorer
urn:nbn:se:umu:diva-182312 (URN)10.1042/BIO20200062 (DOI)2-s2.0-85095758091 (Scopus ID)
Tillgänglig från: 2021-04-19 Skapad: 2021-04-19 Senast uppdaterad: 2023-03-23Bibliografiskt granskad
Rodríguez, M. A., Sandgren Hochhard, K., Vicente, A., Liu, J.-X. & Domellöf, F. P. (2019). Gene expression profile of extraocular muscles following resection strabismus surgery. Experimental Eye Research, 182, 182-193
Öppna denna publikation i ny flik eller fönster >>Gene expression profile of extraocular muscles following resection strabismus surgery
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2019 (Engelska)Ingår i: Experimental Eye Research, ISSN 0014-4835, E-ISSN 1096-0007, Vol. 182, s. 182-193Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

This paper aims to identify key biological processes triggered by resection surgery in the extraocular muscles (EOMs) of a rabbit model of strabismus surgery by studying changes in gene expression. Resection surgery was performed in the superior rectus of 16 rabbits and a group of non-operated rabbits served as control. Muscle samples were collected from groups of four animals 1, 2, 4 and 6 weeks after surgery and processed for RNA-sequencing and immunohistochemistry. We identified a total of 164; 136; 64 and 12 differentially expressed genes 1, 2, 4 and 6 weeks after surgery. Gene Ontology enrichment analysis revealed that differentially expressed genes were involved in biological pathways related to metabolism, response to stimulus mainly related with regulation of immune response, cell cycle and extracellular matrix. A complementary pathway analysis and network analysis performed with Ingenuity Pathway Analysis tool corroborated and completed these findings. Collagen I, fibronectin and versican, evaluated by immunofluorescence, showed that changes at the gene expression level resulted in variation at the protein level. Tenascin-C staining in resected muscles demonstrated the formation of new tendon and myotendinous junctions. These data provide new insights about the biological response of the EOMs to resection surgery and may form the basis for future strategies to improve the outcome of strabismus surgery.

Ort, förlag, år, upplaga, sidor
Elsevier, 2019
Nyckelord
Extraocular muscles, Strabismus, Gene expression, Resection surgery
Nationell ämneskategori
Oftalmologi
Identifikatorer
urn:nbn:se:umu:diva-159869 (URN)10.1016/j.exer.2019.03.022 (DOI)000468258300021 ()30953624 (PubMedID)2-s2.0-85063970565 (Scopus ID)
Forskningsfinansiär
Vetenskapsrådet, 2018-02401Västerbottens läns landsting
Tillgänglig från: 2019-06-10 Skapad: 2019-06-10 Senast uppdaterad: 2023-03-23Bibliografiskt granskad
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