Severe myopathy mutations modify the nanomechanics of desmin intermediate filaments

Area of Science:

• Biophysics
• Cell Biology
• Muscle Physiology

Background:

• Mutations in desmin (intermediate filament protein) cause myofibrillar myopathy.
• Disease-causing desmin mutations were previously thought to prevent filament formation.

Purpose of the Study:

• Investigate the in vitro and in vivo assembly of disease-associated desmin mutants.
• Characterize the nanomechanical properties of desmin filaments formed by these mutants.

Main Methods:

• Atomic force microscopy was used to measure the tensile properties of single desmin intermediate filaments.
• Filaments were formed by wild-type and mutant desmin proteins (DesA360P, DesQ389P, DesD399Y).

Main Results:

• Disease-associated desmin mutants DesA360P, DesQ389P, and DesD399Y can form bona fide intermediate filaments.
• DesA360P filaments showed mechanical properties similar to wild-type desmin.
• DesQ389P and DesD399Y filaments exhibited localized variations in tensile properties.

Conclusions:

• Some desmin mutations allow filament assembly but alter filament nanomechanics.
• Altered biophysical properties of desmin filaments may underlie myofibrillar myopathy pathogenesis.
• Desmin filament mechanosensing and mechanotransduction may be compromised by these mutations.