Key result
Arpc5 disruption impairs muscle function and enlarges t-tubules in mice and human triadopathy patients.
Why the study?
Although t-tubules are essential for muscle physiology and abnormal in muscle disorders, the mechanisms mediating t-tubule growth were unknown.
The actomyosin cortex, regulated by Arpc5, controls t-tubule growth and membrane availability, offering a potential pathophysiological mechanism for skeletal muscle disorders.
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“This was a very surprising finding because we did not expect the actin cytoskeleton to prevent the formation of T-tubules. In fact, our original hypothesis was the opposite.”
“By identifying a mechanism that normally prevents excessive T-tubule growth, this study provides a new perspective on how the architecture of muscle fibres is built and maintained.”
Arpc5 regulates t-tubule integrity and muscle function in mice; leaves open its role as a therapeutic target in human triadopathy.
A network of plasma membrane invaginations called t-tubules plays an essential role in controlling calcium release from the endoplasmic reticulum at the triads during muscle contraction. Although the importance of t-tubules for muscle physiology is well established, and abnormalities are found in muscle disorders, the mechanisms that mediate t-tubule growth are unknown. We show that the actomyosin cortex beneath the plasma membrane, regulated by Arp2/3 complexes containing Arpc5, acts as a gatekeeper for the membrane availability during t-tubule growth. Enlarged t-tubules are formed upon disruption of Arpc5, impairing the synchronization between plasma membrane depolarization and calcium release. Knockout of Arpc5 in mouse skeletal muscle results in impaired locomotion and posture. Furthermore, we show that human triadopathy patients and Arpc5 knockout mice accumulate enlarged t-tubules. We propose that cortex-dependent membrane availability affects muscle function, offering a potential pathophysiological mechanism for muscle disorders.
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Pereira et al. (2026) studied Muscle disorders (triadopathy). Arpc5 disruption/knockout was evaluated on t-tubule remodeling and muscle function. Disruption of Arpc5 in mouse skeletal muscle and human triadopathy patients leads to enlarged t-tubules and impaired muscle function.
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