Key result
SALS protein drives formin-dependent sarcomere growth in Drosophila while overexpression triggers myopathy-like actin aggregates.
Why the study?
During striated muscle development, immature sarcomeres must undergo substantial growth in both length and width to reach final size, but the mechanisms coordinating these processes remained unclear.
SALS is essential for both sarcomere elongation and radial growth in Drosophila muscles, and its overexpression models nemaline myopathy-like actin aggregations.
During striated muscle development the first periodically repeated units appear in the premyofibrils, consisting of immature sarcomeres that must undergo a substantial growth both in length and width, to reach their final size. Here we report that, beyond its well established role in sarcomere elongation, the Sarcomere length short (SALS) protein is involved in Z-disc formation and peripheral growth of the sarcomeres. Our protein localization data and loss-of-function studies in the Drosophila indirect flight muscle strongly suggest that radial growth of the sarcomeres is initiated at the Z-disc. As to thin filament elongation, we used a powerful nanoscopy approach to reveal that SALS is subject to a major conformational change during sarcomere development, which might be critical to stop pointed end elongation in the adult muscles. In addition, we demonstrate that the roles of SALS in sarcomere elongation and radial growth are both dependent on formin type of actin assembly factors. Unexpectedly, when SALS is present in excess amounts, it promotes the formation of actin aggregates highly resembling the ones described in nemaline myopathy patients. Collectively, these findings helped to shed light on the complex mechanisms of SALS during the coordinated elongation and thickening of the sarcomeres, and resulted in the discovery of a potential nemaline myopathy model, suitable for the identification of genetic and small molecule inhibitors.
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Farkas et al. (2024) studied Sarcomere development (Drosophila model). SALS genetic manipulation (knockdown/overexpression) vs. Wild type / control flies was evaluated on Sarcomere length and width. In a Drosophila model, the SALS protein promoted both sarcomere elongation and radial growth in a formin-dependent manner, while its overexpression induced actin aggregates resembling nemaline myopathy.
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