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Congenital myopathy-causing tropomyosin mutations induce thin filament dysfunction via distinct physiological mechanisms
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
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2012 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 21, no 20, 4473-4485 p.Article in journal (Refereed) Published
Abstract [en]

In humans, congenital myopathy-linked tropomyosin mutations lead to skeletal muscle dysfunction, but the cellular and molecular mechanisms underlying such dysfunction remain obscure. Recent studies have suggested a unifying mechanism by which tropomyosin mutations partially inhibit thin filament activation and prevent proper formation and cycling of myosin cross-bridges, inducing force deficits at the fiber and whole-muscle levels. Here, we aimed to verify this mechanism using single membrane-permeabilized fibers from patients with three tropomyosin mutations (TPM2-null, TPM3-R167H and TPM2-E181K) and measuring a broad range of parameters. Interestingly, we identified two divergent, mutation-specific pathophysiological mechanisms. (i) The TPM2-null and TPM3-R167H mutations both decreased cooperative thin filament activation in combination with reductions in the myosin cross-bridge number and force production. The TPM3-R167H mutation also induced a concomitant reduction in thin filament length. (ii) In contrast, the TPM2-E181K mutation increased thin filament activation, cross-bridge binding and force generation. In the former mechanism, modulating thin filament activation by administering troponin activators (CK-1909178 and EMD 57033) to single membrane-permeabilized fibers carrying tropomyosin mutations rescued the thin filament activation defect associated with the pathophysiology. Therefore, administration of troponin activators may constitute a promising therapeutic approach in the future.

Place, publisher, year, edition, pages
2012. Vol. 21, no 20, 4473-4485 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-184452DOI: 10.1093/hmg/dds289ISI: 000309460300009OAI: oai:DiVA.org:uu-184452DiVA: diva2:566731
Available from: 2012-11-09 Created: 2012-11-07 Last updated: 2012-11-09Bibliographically approved

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Ochala, Julien
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