Lamin Mutations Cause Increased YAP Nuclear Entry in Muscle Stem Cells

Abstract

Mutations in the LMNA gene, encoding the nuclear envelope A-type lamins, are responsible for muscular dystrophies, the most severe form being the LMNA-related congenital muscular dystrophy (L-CMD), with severe defects in myonucleus integrity. We previously reported that L-CMD mutations compromise the ability of muscle stem cells to modulate the yes-associated protein (YAP), a pivotal factor in mechanotransduction and myogenesis. Here, we investigated the intrinsic mechanisms by which lamins influence YAP subcellular distribution, by analyzing different conditions affecting the balance between nuclear import and export of YAP. In contrast to wild type (WT) cells, LMNADK32 mutations failed to exclude YAP from the nucleus and to inactivate its transcriptional activity at high cell density, despite activation of the Hippo pathway. Inhibiting nuclear pore import abolished YAP nuclear accumulation in confluent mutant cells, thus showing persistent nuclear import of YAP at cell confluence. YAP deregulation was also present in congenital myopathy related to nesprin-1 KASH mutation, but not in cells expressing the LMNAH222P mutation, the adult form of lamin-related muscle dystrophy with reduced nuclear deformability. In conclusion, our data showed that L-CMD mutations increased YAP nuclear localization via an increased nuclear import and implicated YAP as a pathogenic contributor in muscle dystrophies caused by nuclear envelop defects.

EDMD-Causing Emerin Mutant Myogenic Progenitors Exhibit Impaired Differentiation Using Similar Mechanisms

“…Interestingly, sustained Taz upregulation enhances terminal differentiation of myoblasts in vitro and in vivo [87][88][89]. Yap was recently shown to contribute to the pathogenesis in muscular dystrophy, as increased nuclear localization of Yap is seen in lamin-A-related congenital muscular dystrophy (L-CMD) [90]. Our analysis also revealed significant upregulation of Yap expression and activity along with upregulation of several other pathways' components in the EDMD-causing emerin mutants, suggesting there is increased Yap localization in the nucleus that promotes proliferation activity and inhibits the differentiation program [83].…”

Large-scale curvature sensing by epithelial monolayers depends on active cell mechanics and nuclear mechanoadaptation

“…In addition to YAP response, our results also indicated that lamin A/C ratio 42,43 44 , which would be a natural next step of investigation. Our study therefore provides insights into the mechanistic regulation of epithelial monolayers to large-scale substrate curvature, with potential impact for a large number of physiological situations, given the ubiquitous presence of curvature in vivo.…”

Lamin A/C Mechanotransduction in Laminopathies

“…For instance, atrial cardiac defect-affected myofibroblasts showed reduction of both emerin and SUN2 proteins, supposed to cause the reduced formation of F-actin stress fibers in cyclic stretches condition [244]. Moreover, the same YAP nuclear accumulation previously reported in mutant lamins has been revealed in congenital myopathy with a mutation in nesprin-1 protein [237]. The common element to all the laminopathies would thus appear to be deregulated cell functionality induced by impaired mechanotransduction.…”

“…On the other hand, the lamina pathological activity affects the translocation of nuclear molecules, as demonstrated in congenital muscular dystrophy, where its impaired sensitivity causes an altered activation of YAP signaling [8,143]. Congenital muscular dystrophy-related cells have been correlated to increased YAP nuclear localization due to increased nuclear import, induced by nuclear envelope defect [237]. Likewise, EDMD mice models show enhanced nuclear translocation of activated extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK).…”