Mutations in the intermediate filament (IF) protein desmin cause severe forms of 
myofibrillar myopathy characterized by partial aggregation of the 
extrasarcomeric desmin cytoskeleton and structural disorganization of 
myofibrils. In contrast to prior expectations, we showed that some of the known 
disease-causing mutations, such as DesA360P, DesQ389P and DesD399Y, are 
assembly-competent and do allow formation of bona fide IFs in vitro and in vivo. 
We also previously demonstrated that atomic force microscopy can be employed to 
measure the tensile properties of single desmin IFs. Using the same approach on 
filaments formed by the aforementioned mutant desmins, we now observed two 
different nanomechanical behaviors: DesA360P exhibited tensile properties 
similar to that of wild-type desmin IFs, whereas DesQ389P and DesD399Y exhibited 
local variations in their tensile properties along the filament length. Based on 
these findings, we hypothesize that DesQ389P and DesD399Y may cause muscle 
disease by altering the specific biophysical properties of the desmin filaments, 
thereby compromising both its mechanosensing and mechanotransduction ability.