Translocation of molecular chaperones to the titin springs is common in skeletal myopathy patients and affects sarcomere function
Abstract Summary Myopathies encompass a wide variety of acquired and hereditary disorders. The pathomechanisms include structural and functional changes affecting, e.g., myofiber metabolism and contractile properties. In this study, we observed increased passive tension (PT) of skinned myofibers fro...
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BMC
2017-09-01
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| Series: | Acta Neuropathologica Communications |
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| Online Access: | http://link.springer.com/article/10.1186/s40478-017-0474-0 |
| _version_ | 1819110588559654912 |
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| author | Andreas Unger Lisa Beckendorf Pierre Böhme Rudolf Kley Marion von Frieling-Salewsky Hanns Lochmüller Rolf Schröder Dieter O. Fürst Matthias Vorgerd Wolfgang A. Linke |
| author_facet | Andreas Unger Lisa Beckendorf Pierre Böhme Rudolf Kley Marion von Frieling-Salewsky Hanns Lochmüller Rolf Schröder Dieter O. Fürst Matthias Vorgerd Wolfgang A. Linke |
| author_sort | Andreas Unger |
| collection | DOAJ |
| description | Abstract Summary Myopathies encompass a wide variety of acquired and hereditary disorders. The pathomechanisms include structural and functional changes affecting, e.g., myofiber metabolism and contractile properties. In this study, we observed increased passive tension (PT) of skinned myofibers from patients with myofibrillar myopathy (MFM) caused by FLNC mutations (MFM-filaminopathy) and limb-girdle muscular dystrophy type-2A due to CAPN3 mutations (LGMD2A), compared to healthy control myofibers. Because the giant protein titin determines myofiber PT, we measured its molecular size and the titin-to-myosin ratio, but found no differences between myopathies and controls. All-titin phosphorylation and site-specific phosphorylation in the PEVK region were reduced in myopathy, which would be predicted to lower PT. Electron microscopy revealed extensive ultrastructural changes in myofibers of various hereditary myopathies and also suggested massive binding of proteins to the sarcomeric I-band region, presumably heat shock proteins (HSPs), which can translocate to elastic titin under stress conditions. Correlative immunofluorescence and immunoelectron microscopy showed that two small HSPs (HSP27 and αB-crystallin) and the ATP-dependent chaperone HSP90 translocated to the titin springs in myopathy. The small HSPs, but not HSP90, were upregulated in myopathic versus control muscles. The titin-binding pattern of chaperones was regularly observed in Duchenne muscular dystrophy (DMD), LGMD2A, MFM-filaminopathy, MFM-myotilinopathy, titinopathy, and inclusion body myopathy due to mutations in valosin-containing protein, but not in acquired sporadic inclusion body myositis. The three HSPs also associated with elastic titin in mouse models of DMD and MFM-filaminopathy. Mechanical measurements on skinned human myofibers incubated with exogenous small HSPs suggested that the elevated PT seen in myopathy is caused, in part, by chaperone-binding to the titin springs. Whereas this interaction may be protective in that it prevents sarcomeric protein aggregation, it also has detrimental effects on sarcomere function. Thus, we identified a novel pathological phenomenon common to many hereditary muscle disorders, which involves sarcomeric alterations. |
| first_indexed | 2024-12-22T03:44:06Z |
| format | Article |
| id | doaj.art-3d5217375fc44a34bd739fc04713fabc |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-12-22T03:44:06Z |
| publishDate | 2017-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-3d5217375fc44a34bd739fc04713fabc2022-12-21T18:40:10ZengBMCActa Neuropathologica Communications2051-59602017-09-015111410.1186/s40478-017-0474-0Translocation of molecular chaperones to the titin springs is common in skeletal myopathy patients and affects sarcomere functionAndreas Unger0Lisa Beckendorf1Pierre Böhme2Rudolf Kley3Marion von Frieling-Salewsky4Hanns Lochmüller5Rolf Schröder6Dieter O. Fürst7Matthias Vorgerd8Wolfgang A. Linke9Department of Cardiovascular Physiology, Ruhr University BochumDepartment of Cardiovascular Physiology, Ruhr University BochumDepartment of Neurology, Heimer Institute for Muscle Research, University Hospital Bergmannsheil, Ruhr University BochumDepartment of Neurology, Heimer Institute for Muscle Research, University Hospital Bergmannsheil, Ruhr University BochumInstitute of Physiology II, University of MuensterInstitute of Genetic Medicine, Newcastle University, International Centre for Life, Central ParkwayInstitute of Neuropathology and Department of Neurology, University Hospital ErlangenInstitute for Cell Biology, Department of Molecular Cell Biology, University of BonnDepartment of Neurology, Heimer Institute for Muscle Research, University Hospital Bergmannsheil, Ruhr University BochumDepartment of Cardiovascular Physiology, Ruhr University BochumAbstract Summary Myopathies encompass a wide variety of acquired and hereditary disorders. The pathomechanisms include structural and functional changes affecting, e.g., myofiber metabolism and contractile properties. In this study, we observed increased passive tension (PT) of skinned myofibers from patients with myofibrillar myopathy (MFM) caused by FLNC mutations (MFM-filaminopathy) and limb-girdle muscular dystrophy type-2A due to CAPN3 mutations (LGMD2A), compared to healthy control myofibers. Because the giant protein titin determines myofiber PT, we measured its molecular size and the titin-to-myosin ratio, but found no differences between myopathies and controls. All-titin phosphorylation and site-specific phosphorylation in the PEVK region were reduced in myopathy, which would be predicted to lower PT. Electron microscopy revealed extensive ultrastructural changes in myofibers of various hereditary myopathies and also suggested massive binding of proteins to the sarcomeric I-band region, presumably heat shock proteins (HSPs), which can translocate to elastic titin under stress conditions. Correlative immunofluorescence and immunoelectron microscopy showed that two small HSPs (HSP27 and αB-crystallin) and the ATP-dependent chaperone HSP90 translocated to the titin springs in myopathy. The small HSPs, but not HSP90, were upregulated in myopathic versus control muscles. The titin-binding pattern of chaperones was regularly observed in Duchenne muscular dystrophy (DMD), LGMD2A, MFM-filaminopathy, MFM-myotilinopathy, titinopathy, and inclusion body myopathy due to mutations in valosin-containing protein, but not in acquired sporadic inclusion body myositis. The three HSPs also associated with elastic titin in mouse models of DMD and MFM-filaminopathy. Mechanical measurements on skinned human myofibers incubated with exogenous small HSPs suggested that the elevated PT seen in myopathy is caused, in part, by chaperone-binding to the titin springs. Whereas this interaction may be protective in that it prevents sarcomeric protein aggregation, it also has detrimental effects on sarcomere function. Thus, we identified a novel pathological phenomenon common to many hereditary muscle disorders, which involves sarcomeric alterations.http://link.springer.com/article/10.1186/s40478-017-0474-0Myofibrillar myopathyMuscular dystrophyMuscle stiffnessMolecular chaperonesImmunoelectron microscopy |
| spellingShingle | Andreas Unger Lisa Beckendorf Pierre Böhme Rudolf Kley Marion von Frieling-Salewsky Hanns Lochmüller Rolf Schröder Dieter O. Fürst Matthias Vorgerd Wolfgang A. Linke Translocation of molecular chaperones to the titin springs is common in skeletal myopathy patients and affects sarcomere function Acta Neuropathologica Communications Myofibrillar myopathy Muscular dystrophy Muscle stiffness Molecular chaperones Immunoelectron microscopy |
| title | Translocation of molecular chaperones to the titin springs is common in skeletal myopathy patients and affects sarcomere function |
| title_full | Translocation of molecular chaperones to the titin springs is common in skeletal myopathy patients and affects sarcomere function |
| title_fullStr | Translocation of molecular chaperones to the titin springs is common in skeletal myopathy patients and affects sarcomere function |
| title_full_unstemmed | Translocation of molecular chaperones to the titin springs is common in skeletal myopathy patients and affects sarcomere function |
| title_short | Translocation of molecular chaperones to the titin springs is common in skeletal myopathy patients and affects sarcomere function |
| title_sort | translocation of molecular chaperones to the titin springs is common in skeletal myopathy patients and affects sarcomere function |
| topic | Myofibrillar myopathy Muscular dystrophy Muscle stiffness Molecular chaperones Immunoelectron microscopy |
| url | http://link.springer.com/article/10.1186/s40478-017-0474-0 |
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