Key result
stac3 knockout in zebrafish larvae significantly reduced hatching at 4 days post-fertilization (12% vs 76.7% in controls) and led to elevated neutral lipids, phenocopying Native American myopathy.
Why the study?
Whether elevated neutral lipids alter muscle function via the excitation-contraction coupling apparatus during early development in Native American myopathy was undiscovered.
Absolute Event Rate: 12% vs 76.7%
p-value: p=<0.05
The stac3 knockout zebrafish model phenocopies Native American myopathy, demonstrating that loss of stac3 leads to early life lipid overload, calcium deficiency, and muscle weakness.
Provides a novel zebrafish model for Native American myopathy; extends mechanistic insights but leaves open translation to human therapies.
Understanding the early stages of human congenital myopathies is critical for proposing strategies for improving skeletal muscle performance by the functional integrity of cytoskeleton. SH3 and cysteine-rich domain 3 (Stac3) is a protein involved in nutrient sensing, and is an essential component of the excitation-contraction (EC) coupling machinery for Ca 2+ releasing. A mutation in STAC3 causes debilitating Native American myopathy (NAM) in humans, and loss of this gene in mice and zebrafish resulted in death in early life. Previously, NAM patients demonstrated increased lipids in skeletal muscle biopsy. However, elevated neutral lipids could alter muscle function in NAM disease via EC coupling apparatus is yet undiscovered in early development. Here, using a CRISPR/Cas9 induced stac3 knockout (KO) zebrafish model, we determined that loss of stac3 led to muscle weakness, as evidenced by delayed larval hatching. We observed decreased whole-body Ca 2+ level at 5 days post-fertilization (dpf) and defects in the skeletal muscle cytoskeleton, i.e., F-actin and slow muscle fibers at 5 and 7 dpf. Homozygous larvae exhibited elevated neutral lipid levels at 5 dpf, which persisted beyond 7 dpf. Myogenesis regulators such as myoD and myf5 , were significantly altered in stac3 -/- larvae at 5 dpf, thus a progressive death of the KO larva by 11 dpf. In summary, the presented findings suggest that stac3 -/- can serve as a non-mammalian model to identify lipid-lowering molecules for refining muscle function in NAM patients.
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Donaka et al. (2023) studied Native American myopathy. stac3 knockout vs. stac3+/+ and stac3+/- siblings was evaluated on Hatching percentage at 4 days post-fertilization (p=<0.05). stac3 knockout in zebrafish larvae significantly reduced hatching at 4 days post-fertilization (12% vs 76.7% in controls) and led to elevated neutral lipids, phenocopying Native American myopathy.
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