Tropomodulin isoforms regulate thin filament pointed-end capping and skeletal muscle physiology

DS Gokhin, RA Lewis, CR McKeown, RB Nowak… - Journal of cell …, 2010 - rupress.org
DS Gokhin, RA Lewis, CR McKeown, RB Nowak, NE Kim, RS Littlefield, RL Lieber
Journal of cell biology, 2010rupress.org
During myofibril assembly, thin filament lengths are precisely specified to optimize skeletal
muscle function. Tropomodulins (Tmods) are capping proteins that specify thin filament
lengths by controlling actin dynamics at pointed ends. In this study, we use a genetic
targeting approach to explore the effects of deleting Tmod1 from skeletal muscle. Myofibril
assembly, skeletal muscle structure, and thin filament lengths are normal in the absence of
Tmod1. Tmod4 localizes to thin filament pointed ends in Tmod1-null embryonic muscle …
During myofibril assembly, thin filament lengths are precisely specified to optimize skeletal muscle function. Tropomodulins (Tmods) are capping proteins that specify thin filament lengths by controlling actin dynamics at pointed ends. In this study, we use a genetic targeting approach to explore the effects of deleting Tmod1 from skeletal muscle. Myofibril assembly, skeletal muscle structure, and thin filament lengths are normal in the absence of Tmod1. Tmod4 localizes to thin filament pointed ends in Tmod1-null embryonic muscle, whereas both Tmod3 and -4 localize to pointed ends in Tmod1-null adult muscle. Substitution by Tmod3 and -4 occurs despite their weaker interactions with striated muscle tropomyosins. However, the absence of Tmod1 results in depressed isometric stress production during muscle contraction, systemic locomotor deficits, and a shift to a faster fiber type distribution. Thus, Tmod3 and -4 compensate for the absence of Tmod1 structurally but not functionally. We conclude that Tmod1 is a novel regulator of skeletal muscle physiology.
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