Journal
HUMAN MOLECULAR GENETICS
Volume 21, Issue 20, Pages 4473-4485Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/dds289
Keywords
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Funding
- Swedish Research Council
- Association Francaise contre les Myopathies
- Tore Nilson Stiftelse
- Stiftelsen Apotekare Hedbergs fond for Medicinsk Forskning
- NIH from the National Institute of Arthritis and Musculoskeletal and Skin Diseases at the National Institutes of Health [P30-AR061303]
- National Heart, Lung, and Blood Institute at the National Institutes of Health [T32-HL007195]
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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.
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