Journal
HUMAN MOLECULAR GENETICS
Volume 24, Issue 22, Pages 6278-6292Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddv334
Keywords
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Funding
- National Health and Medical Research Council of Australia [APP571287, APP1022707, APP1048816, APP1035955]
- National Institutes of Health (USA) from the National Institute of Child Health and Human Development [R01 HD075802]
- University of Sydney Australian Postgraduate Award
- International Postgraduate Research Scholarship
- Boehringer Ingelheim Fonds Travel Grant
- Australian Resource Council [FT100100734]
- British Heart Foundation [RG/11/20/29266, FS/12/24/29568] Funding Source: researchfish
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Dominant mutations in TPM3, encoding alpha-tropomyosin(slow), cause a congenital myopathy characterized by generalized muscle weakness. Here, we used a multidisciplinary approach to investigate the mechanism of muscle dysfunction in 12 TPM3myopathy patients. We confirm that slow myofibre hypotrophy is a diagnostic hallmark of TPM3-myopathy, and is commonly accompanied by skewing of fibre-type ratios (either slow or fast fibre predominance). Patient muscle contained normal ratios of the three tropomyosin isoforms and normal fibre-type expression of myosins and troponins. Using 2D-PAGE, we demonstrate that mutant alpha-tropomyosin(slow) was expressed, suggesting muscle dysfunction is due to a dominant-negative effect of mutant protein on muscle contraction. Molecular modelling suggested mutant alpha-tropomyosin(slow) likely impacts actin-tropomyosin interactions and, indeed, co-sedimentation assays showed reduced binding of mutant alpha-tropomyosin(slow) (R168C) to filamentous actin. Single fibre contractility studies of patient myofibres revealed marked slow myofibre specific abnormalities. At saturating [Ca2+] (pCa 4.5), patient slow fibres produced only 63% of the contractile force produced in control slow fibres and had reduced acto-myosin cross-bridge cycling kinetics. Importantly, due to reduced Ca2+-sensitivity, at sub-saturating [Ca2+] (pCa 6, levels typically released during in vivo contraction) patient slow fibres produced only 26% of the force generated by control slow fibres. Thus, weakness in TPM3-myopathy patients can be directly attributed to reduced slow fibre force at physiological [Ca2+], and impaired acto-myosin cross-bridge cycling kinetics. Fastmyofibres are spared; however, they appear to be unable to compensate for slow fibre dysfunction. Abnormal Ca2+-sensitivity in TPM3-myopathy patients suggests Ca2+-sensitizing drugs may represent a useful treatment for this condition.
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