Key result
Homozygous lmna mutant zebrafish exhibited prominent skeletal muscle abnormalities and a 1.26-fold increase in activated Erk 1/2 protein compared to wild type at 7 days post-fertilization.
Why the study?
LMNA mutations frequently cause striated muscle laminopathies involving cardiac and/or skeletal muscle diseases.
Effect estimate: 1.26-fold increase
This novel zebrafish model of muscular laminopathy exhibits early skeletal muscle abnormalities and is the first to potentially implicate Pkc α in the disease process.
This zebrafish laminopathy model enables mechanistic studies; leaves open Pkc α as a therapeutic target pending mammalian validation.
BACKGROUND: Lamin A/C gene (LMNA) mutations frequently cause cardiac and/or skeletal muscle diseases called striated muscle laminopathies. We created a zebrafish muscular laminopathy model using CRISPR/Cas9 technology to target the zebrafish lmna gene. RESULTS: Heterozygous and homozygous lmna mutants present skeletal muscle damage at 1 day post-fertilization (dpf), and mobility impairment at 4 to 7 dpf. Cardiac structure and function analyses between 1 and 7 dpf show mild and transient defects in the lmna mutants compared to wild type (WT). Quantitative RT-PCR analysis of genes implicated in striated muscle laminopathies show a decrease in jun and nfκb2 expression in 7 dpf homozygous lmna mutants compared to WT. Homozygous lmna mutants have a 1.26-fold protein increase in activated Erk 1/2, kinases associated with striated muscle laminopathies, compared to WT at 7 dpf. Activated Protein Kinase C alpha (Pkc α), a kinase that interacts with lamin A/C and Erk 1/2, is also upregulated in 7 dpf homozygous lmna mutants compared to WT. CONCLUSIONS: This study presents an animal model of skeletal muscle laminopathy where heterozygous and homozygous lmna mutants exhibit prominent skeletal muscle abnormalities during the first week of development. Furthermore, this is the first animal model that potentially implicates Pkc α in muscular laminopathies.
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Nicolas et al. (2021) studied Striated muscle laminopathies. CRISPR/Cas9 targeted lmna mutation vs. Wild type (WT) was evaluated on Skeletal muscle damage, mobility impairment, and protein expression (1.26-fold increase). Homozygous lmna mutant zebrafish exhibited prominent skeletal muscle abnormalities and a 1.26-fold increase in activated Erk 1/2 protein compared to wild type at 7 days post-fertilization.
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