Drosophila Tropomodulin is required for multiple actin-dependent processes in myofiber assembly and maintenance

Abstract

Proper muscle contraction requires the assembly and maintenance of sarcomeres and myofibrils. While the protein components of myofibrils are generally known, less is known about the mechanisms by which they individually function and together synergize for myofibril assembly and maintenance. For example, it is unclear how the disruption of actin filament (F-actin) regulatory proteins leads to the muscle weakness observed in myopathies. Here, we show that knockdown of Drosophila Tropomodulin (Tmod), a F-actin pointed-end capping protein, results in several myopathy-related phenotypes, including reduction of muscle cell (myofiber) size, increased sarcomere length, disorganization and misorientation of myofibrils, ectopic F-actin accumulation, loss of tension-mediating proteins at the myotendinous junction, and misshaped and internalized nuclei. Our findings support and extend the tension-driven self-organization myofibrillogenesis model. We show that, like its mammalian counterpart, Drosophila Tmod caps filament pointed ends, and this activity is critical for cellular processes in different locations within the myofiber that directly and indirectly contribute to the maintenance of muscle function. Our findings provide significant insights to the role of Tmod in muscle development, maintenance, and disease.