Key result
Loss-of-function mutations in lmod3 and capza1b in zebrafish caused reduced muscle integrity and myofibril defects at peripheral myofiber ends, indicating a role in longitudinal myofibril growth.
Why the study?
Mutations in sarcomere components cause human disease, but the complex process of sarcomere assembly is not fully understood.
CapZα and Leiomodin 3 are not essential for initial myofibril assembly but function in the longitudinal growth of the contractile apparatus.
Leiomodin-3's role in myofibril growth refines sarcomere models; leaves open cardiac disease relevance and clinical translation.
Myofibrils within skeletal muscle are composed of sarcomeres that generate force by contraction when their myosin-rich thick filaments slide past actin-based thin filaments. Although mutations in components of the sarcomere are a major cause of human disease, the highly complex process of sarcomere assembly is not fully understood. Current models of thin filament assembly highlight a central role for filament capping proteins, which can be divided into three protein families, each ascribed with separate roles in thin filament assembly. CapZ proteins have been shown to bind the Z-disc protein α-actinin to form an anchoring complex for thin filaments and actin polymerisation. Subsequent thin filaments extension dynamics are thought to be facilitated by Leiomodins (Lmods) and thin filament assembly is concluded by Tropomodulins (Tmods) that specifically cap the pointed end of thin filaments. To study thin filament assembly in vivo, single and compound loss-of-function zebrafish mutants within distinct classes of capping proteins were analysed. The generated lmod3- and capza1b-deficient zebrafish exhibited aspects of the pathology caused by variations in their human orthologs. Although loss of the analysed main capping proteins of the skeletal muscle, capza1b, capza1a, lmod3 and tmod4, resulted in sarcomere defects, residual organised sarcomeres were formed within the assessed mutants, indicating that these proteins are not essential for the initial myofibril assembly. Furthermore, detected similarity and location of myofibril defects, apparent at the peripheral ends of myofibres of both Lmod3- and CapZα-deficient mutants, suggest a function in longitudinal myofibril growth for both proteins, which is molecularly distinct to the function of Tmod4.
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Berger et al. (2022) studied Myopathy (zebrafish model). Loss-of-function mutations in capping proteins (lmod3, capza1a, capza1b, tmod4) vs. Wildtype siblings was evaluated on Muscle integrity (birefringence) and active force generation. Loss-of-function mutations in lmod3 and capza1b in zebrafish caused reduced muscle integrity and myofibril defects at peripheral myofiber ends, indicating a role in longitudinal myofibril growth.
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