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Dominant mutations in  TPM3 , encoding α-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  TPM3 -myopathy 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 α-tropomyosin slow  was expressed, suggesting muscle dysfunction is due to a dominant-negative effect of mutant protein on muscle contraction. Molecular modelling suggested mutant α-tropomyosin slow  likely impacts actin–tropomyosin interactions and, indeed, co-sedimentation assays showed reduced binding of mutant α-tropomyosin slow  (R168C) to filamentous actin. Single fibre contractility studies of patient myofibres revealed marked slow myofibre specific abnormalities. At saturating [Ca 2+ ] (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 Ca 2+ -sensitivity, at sub-saturating [Ca 2+ ] (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 [Ca 2+ ], and impaired acto-myosin cross-bridge cycling kinetics. Fast myofibres are spared; however, they appear to be unable to compensate for slow fibre dysfunction. Abnormal Ca 2+ -sensitivity in  TPM3 -myopathy patients suggests Ca 2+ -sensitizing drugs may represent a useful treatment for this condition.

Muscle weakness in TPM3 -myopathy is due to reduced Ca 2+ -sensitivity and impaired acto-myosin cross-bridge cycling in slow fibres