Control of thin filament lengths by sarcomeric tropomodulin isoforms: insights from mouse models (1102.2)

Abstract

The uniform lengths of skeletal muscle thin filaments are controlled by actin subunit exchange at pointed ends (P‐ends). Each P‐end is capped by two sarcomeric tropomodulin (Tmod) molecules, with Tmod1 and Tmod4 isoforms present in a 1:9 ratio. In Tmod1‐null sarcomeres, P‐ends are capped by Tmod3 (normally a sarcoplasmic reticulum‐associated Tmod isoform) and Tmod4, preserving normal thin filament lengths. In Tmod4‐null sarcomeres, P‐ends are capped solely by Tmod1, also preserving normal lengths. The mild phenotypes of Tmod1‐null and Tmod4‐null muscle highlight skeletal muscle’s ability to deploy compensatory mechanisms to specify correct thin filament lengths in the absence of one sarcomeric Tmod isoform during myofibril assembly and muscle development. To discern the effect of sarcomeric Tmod depletion from mature muscle, we measured thin filament lengths in the mdx and mdx/mTR mouse models of Duchenne muscular dystrophy, in which Tmods are calpain‐proteolyzed in a muscle use‐dependent manner. Proteolysis of Tmod1 and/or Tmod4 in mdx and mdx/mTR muscles results in 10‐12% increases in thin filament lengths, due to addition of actin subunits onto P‐ends. Collectively, these results show that Tmod1 and Tmod4 are individually dispensable for initial specification of muscle‐specific thin filament lengths, but important for maintenance of correct thin filament lengths in mature contracting myofibrils.Grant Funding Source: Supported by NIH and MDA.