Titin-based stiffening of muscle fibers in Ehlers-Danlos Syndrome
Open accessAbstract
OBJECTIVE: tenascin-X (TNX) is an extracellular matrix glycoprotein whose absence leads to Ehlers-Danlos Syndrome (EDS). TNX-deficient EDS patients present with joint hypermobility and muscle weakness attributable to increased compliance of the extracellular matrix. We hypothesized that in response to the increased compliance of the extracellular matrix in TNX-deficient EDS patients, intracellular adaptations take place in the elastic properties of the giant muscle protein titin. METHODS: we performed extensive single muscle fiber mechanical studies to determine active and passive properties in TNX-deficient EDS patients. Gel-electrophoresis, Western blotting, and microarray studies were used to evaluate titin expression and phosphorylation. X-ray diffraction was used to measure myofilament lattice spacing. RESULTS: passive tension of muscle fibers from TNX-deficient EDS patients was markedly increased. Myofilament extraction experiments indicated that the increased passive tension is attributable to changes in the properties of the sarcomeric protein titin. Transcript and protein data indicated no changes in titin isoform expression. Instead, differences in posttranslational modifications within titin's elastic region were found. In patients, active tension was not different at maximal activation level, but at submaximal activation level it was augmented attributable to increased calcium sensitivity. This increased calcium sensitivity might be attributable to stiffer titin molecules. CONCLUSION: in response to the increased compliance of the extracellular matrix in muscle of TNX-deficient EDS patients, a marked intracellular stiffening occurs of the giant protein titin. The stiffening of titin partly compensates for the muscle weakness in these patients by augmenting submaximal active tension generation.
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All papers describing research concerning muscular function in TNX-deficiency or their muscle tissue conclude that there is some degree of muscle weakness in patients with TNX-deficiency.
“All papers conclude that there is some degree of muscle weakness in patients with TNX-deficiency.”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Ottenheijm et al., 2012
The stiffening of titin most likely compensates for the muscle weakness in TNX-deficient EDS.
“The stiffening of titin most likely compensates for the muscle weakness [Ottenheijm et al., 2012].”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Ottenheijm et al., 2012
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- Authors
- Ottenheijm, C. A. C., Voermans, N. C., Hudson, B. D., Irving, T., Stienen, G. J. M., van Engelen, B. G., & Granzier, H.
- Affiliations
- University of Arizona (US)
- Radboud University Nijmegen (NL)
- Illinois Institute of Technology (US)
- Amsterdam Cardiovascular Sciences (NL)
- Department of Neurology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands;
- Corresponding author
- Ottenheijm, Coen A. C.
- Venue
- Journal of Applied Physiology
- Publisher
- American Physiological Society
- Published
- 2012-04-01
- Volume
- 112
- Issue
- 7
- Pages
- 1157-1165
- ISSN
- 0161-7567 (ISSN-L)
- 8750-7587
- 1522-1601
- PMC
- PMC3774215
- OpenAlex
- W2095681672
- Cited by
- 40
- References
- 41
- Citations by year
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- FWCI
- 1.93
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Journal of Applied Physiology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Radboud Universitair Medisch Centrum
- National Heart, Lung, and Blood Institute (T32HL007249)
- National Institute of General Medical Sciences (P41GM103622)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR060697)
- National Center for Research Resources (P41RR008630)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
- Keywords
- Ehlers-Danlos syndrome, titin, muscle stiffness, passive tension, muscle fiber mechanics, titin phosphorylation, calcium sensitivity, muscle weakness
- MeSH terms
- Adenosine Triphosphatases, Adenosine Triphosphate, Adult, Biomechanical Phenomena, Ehlers-Danlos Syndrome, Elasticity, Electrophoresis, Polyacrylamide Gel, Extracellular Matrix, Female, Humans, Male, Muscle Contraction, Muscle Proteins, Myofibrils, Protein Kinases, Sarcomeres, X-Ray Diffraction, Blotting, Western, Muscle Fibers, Skeletal, Muscle Weakness, Tenascin, Calcium Signaling, Microarray Analysis, Young Adult, Connectin, In Vitro Techniques
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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