Fragile hearts: new insights into translational control in cardiac muscle

Abstract

Current investigations focused on RNA-binding proteins in striated muscle, which provide a scenario whereby muscle function and development are governed by the interplay of post-transcriptional RNA regulation, including transcript localization, splicing, stability, and translational control. New data have recently emerged, linking the RNA-binding protein FXR1 to the translation of key cytoskeletal components such as talin and desmoplakin in heart muscle. These findings, together with a plethora of recent reports implicating RNA-binding proteins and their RNA targets in both basic aspects of muscle development and differentiation as well as heart disease and muscular dystrophies, point to a critical role of RNA-based regulatory mechanisms in muscle biology. Here we focus on FXR1, the striated muscle-specific member of the Fragile X family of RNA-binding proteins and discuss its newly reported cytoskeletal targets as well as potential implications for heart disease.

Fig. 1

Model for localized translation/co-translational assembly in heart muscle. FXR1 (and other RNA-binding proteins, not shown) associate with target mRNAs in the nucleus. Protein-mRNA complexes are exported into the sarcoplasm and localized in the vicinity of local translation sites (marked by ribosomes). Regulatory mechanisms include mRNA transport and stability. mRNA anchoring may be controlled as well (not shown). Next, through the coupling of localization and translation processes, newly synthesized peptides assemble directly into complex cytoskeletal assemblies such as the sarcomere. (Color version of figure is available online.)

Fig 2

FXR1 protein structure. FXR1 is a nucleo-cytoplasmic shuttling protein and is comprised of 3 RNA-binding domains: KH1, KH2, and RGG (as shown). For more information on the other protein motifs, see text. (Color version of figure is available online.)

Fig. 3

FXR1 is required for the structural integrity of junctional complexes and sarcomeres in the heart. (A and B) Electron micrographs of E18.5 mouse heart wild-type myofibrils (A) exhibit well-organized sarcomeres with tightly bundled filaments and parallel evenly spaced, narrow Z-discs (red arrows) compared with misaligned Fxr1 KO myofibrils (B), which contain shorter sarcomeres with broad Z-discs and less organized thick filaments (arrows denote Z-discs). (C and D) View of the inner dense plaque of desmosomes in wild-type (C) versus Fxr1 KO (D) E18.5 hearts. Note prominent electron dense material in wild-type (delineated by arrowheads), where intermediate filaments anchor to the desmosomal membrane compared with the inner reduced plaques in the KO hearts. (E) Schematic of cytoskeletal assemblies in heart muscle. Proteins in bold are reported targets of FXR1.