Muscle weakness in TPM3-myopathy is due to reduced Ca2 -sensitivity and impaired acto-myosin cross-bridge cycling in slow fibres

Abstract

Dominant mutations in TPM3, encoding a-tropomyosinslow, 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 a-tropomyosinslow was expressed, suggesting muscle dysfunction is due to a dominant-neg..