A cytoskeletal tropomyosin can compromise the structural integrity of skeletal muscle

Abstract

We have identified a number of extra-sarcomeric actin filaments defined by cytoskeletal tropomyosin (Tm) isoforms. Expression of a cytoskeletal Tm (Tm3) not normally present in skeletal muscle in a transgenic mouse resulted in muscular dystrophy. In the present report we show that muscle pathology in this mouse is late onset (between 2 and 6 months of age) and is predominately in the back and paraspinal muscles. In the Tm3 mice, Evans blue dye uptake in muscle and serum levels of creatine kinase were markedly increased following downhill exercise, and the force drop following a series of lengthening contractions in isolated muscles (extensor digitorum longus) was also significantly increased in these mice. These results demonstrate that expression of an inappropriate Tm in skeletal muscle results in increased susceptibility to contraction-induced damage. The extra-sarcomeric actin cytoskeleton therefore may have an important role in protecting the muscle from contractile stress.

Tropomyosin – master regulator of actin filament function in the cytoskeleton

“…In addition, altered excitation-contractioncoupling has been observed which is consistent with an altered uptake of Ca 2+ through the triad, possibly because of changes in T-tubule function (Vlahovich et al, 2009). In addition, expression of the cytoskeletal Tpm1.7, but not of Tpm3.1, in skeletal muscle results in muscular dystrophy (Kee et al, 2009a). This specificity in the effect of cytoskeletal Tpm isoforms mirrors the studies from D. F.…”

Tropomyosin isoforms and reagents

“…90 The Tm3 transgenic mice demonstrate dystrophic features perhaps due to increase sensitivity to contractile-induced stress. 65,91 In the case of the although the Tm mutations linked to human diseases are known to exhibit clinical abnormalities mostly restricted to the heart and skeletal muscle, these mutations are present in exons shared by numerous other Tm isoforms (see Tables 2 and 3). 85 All known cardiomyopathies carry mutations in Tm isoforms specific to the central nervous system including TmBr1, TmBr2 and TmBr3.…”

New Insights into the Regulation of the Actin Cytoskeleton by Tropomyosin

“…When Tm3 is expressed in mice, rather than associating with the thin filaments in the sarcomere of skeletal muscle, it becomes associated with regions where endogenous cytoplasmic Tms are found, that is, adjacent to the Z-lines in muscle. Expression of this Tm, which is not normally found in skeletal muscle, leads to late onset muscular dystrophy probably by compromising the structural integrity of the muscle (Kee et al, 2004, 2009). During myogenesis, muscle-specific isoforms are induced and cytoskeletal forms are repressed.…”