Key result
Transplanted myoblasts integrate titin locally into host sarcomeres without syncytial-wide diffusion.
Why the study?
The logistics underlying myofilament assembly and disassembly during myocyte fusion have remained incompletely understood, warranting direct visualization of labeled sarcomere components to study skeletal muscle development and cell-based therapies.
The limited diffusion of donor-derived sarcomeric proteins within adult muscle syncytia highlights a significant hurdle for the uniform distribution of therapeutic proteins in cell-based therapies for skeletal muscle diseases.
Nuclear retention of donor titin may constrain uniform protein delivery in myoblast therapies; leaves open strategies to enhance syncytial diffusion.
The giant striated muscle protein titin integrates into the developing sarcomere to form a stable myofilament system that is extended as myocytes fuse. The logistics underlying myofilament assembly and disassembly have started to emerge with the possibility to follow labeled sarcomere components. Here, we generated the mCherry knock-in at titin’s Z-disk to study skeletal muscle development and remodeling. We find titin’s integration into the sarcomere tightly regulated and its unexpected mobility facilitating a homogenous distribution of titin after cell fusion – an integral part of syncytium formation and maturation of skeletal muscle. In adult mCherry-titin mice, treatment of muscle injury by implantation of titin-eGFP myoblasts reveals how myocytes integrate, fuse and contribute to the continuous myofilament system across cell boundaries. Unlike in immature primary cells, titin proteins are retained at the proximal nucleus and do not diffuse across the whole syncytium with implications for future cell-based therapies of skeletal muscle disease.
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Hüttemeister et al. (2024) studied skeletal muscle injury and regeneration. titin-eGFP myoblast implantation vs. Cardiotoxin injury only or cell transplantation without injury was evaluated on Titin distribution, integration, and mobility post-cell fusion. Implantation of titin-eGFP myoblasts into injured adult mCherry-titin mice revealed that titin proteins integrate into host sarcomeres but are retained proximally to the nucleus and do not diffuse across the whole syncytium.
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