Z-Disk-Associated Plectin (Isoform 1d): Spatial Arrangement, Interaction Partners, and Role in Filamin C Homeostasis

Area of Science:

• Muscle biology
• Cellular and molecular biology
• Biochemistry

Background:

• Plectin (PLEC) is a cytolinker protein essential for myofiber integrity.
• Mutations in PLEC cause plectinopathies, leading to muscle weakness.
• Plectin isoform P1d is exclusively expressed in skeletal muscle and heart.

Purpose of the Study:

• To investigate the structural and functional roles of plectin isoform P1d in skeletal muscle.
• To elucidate the involvement of P1d in muscle fiber organization, mechanical properties, and protein homeostasis.

Main Methods:

• High-resolution stimulated emission depletion (STED) microscopy.
• Isoform-specific knockout (P1d-KO) mouse models.
• Mechanical strain on myoblasts.
• Forced swim tests in mice.

Main Results:

• Plectin bridges α-actinin-positive Z-disks to desmin intermediate filaments.
• Loss of P1d causes Z-disk disorganization, muscle fiber inhomogeneity, and slower myofibril relaxation.
• P1d acts as a scaffold for chaperone-assisted selective autophagy (CASA), interacting with HSC70 and synpo2.
• P1d deficiency leads to accumulation of undigested filamin C, especially under mechanical stress and exercise.

Conclusions:

• Plectin isoform P1d is critical for myofiber structural integrity and mechanical response.
• P1d plays a key role in tension-induced proteolysis via the CASA pathway, preventing filamin C aggregation during strenuous activity.