The link between the cytoplasmic desmin intermediate filaments and those of 
nuclear lamins serves as a major integrator point for the intracellular 
communication between the nucleus and the cytoplasm in cardiac muscle. We 
investigated the involvement of desmin in the cardiomyopathy caused by the lamin 
A/C gene mutation using the LmnaH222P/H222P mouse model of the disease. We 
demonstrate that in these mouse hearts desmin loses its normal Z disk and 
intercalated disc localization and presents aggregate formation along with 
mislocalization of basic intercalated disc protein components, as well as severe 
structural abnormalities of the intercalated discs and mitochondria. To address 
the extent by which the observed desmin network defects contribute to the 
progression of LmnaH222P/H222P cardiomyopathy, we investigated the consequences 
of desmin-targeted approaches for the disease treatment. We showed that 
cardiac-specific overexpression of the small heat shock protein αΒ-Crystallin 
confers cardioprotection in LmnaH222P/H222P mice by ameliorating desmin network 
defects and by attenuating the desmin-dependent mislocalization of basic 
intercalated disc protein components. In addition, αΒ-Crystallin overexpression 
rescues the intercalated disc, mitochondrial and nuclear defects of 
LmnaH222P/H222P hearts, as well as the abnormal activation of ERK1/2. Consistent 
with that, by generating the LmnaH222P/H222PDes+/- mice, we showed that the 
genetically decreased endogenous desmin levels have cardioprotective effects in 
LmnaH222P/H222P hearts since less desmin is available to form dysfunctional 
aggregates. In conclusion, our results demonstrate that desmin network 
disruption, disorganization of intercalated discs and mitochondrial defects are 
a major mechanism contributing to the progression of this LMNA cardiomyopathy 
and can be ameliorated by αΒ-Crystallin overexpression.