Hippo signaling pathway is altered in Duchenne muscular dystrophy

Abstract

Hippo signaling pathway is considered a key regulator of tissue homeostasis, cell proliferation, apoptosis and it is involved in cancer development. In skeletal muscle, YAP, a downstream target of the Hippo pathway, is an important player in myoblast proliferation, atrophy/hypertrophy regulation, and in mechano-trasduction, transferring mechanical signals into transcriptional responses. We studied components of Hippo pathway in muscle specimens from patients with Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, limb-girdle muscular dystrophy type 2A and type 2B and healthy subjects. Only DMD muscles had decreased YAP1 protein expression, increased LATS1/2 kinase activity, low Survivin mRNA expression and high miR-21 expression. In light of our novel results, a schematic model is postulated: low levels of YOD1 caused by increased inhibition by miR-21 lead to an increase of LATS1/2 activity which in turn augments phosphorylation of YAP. Reduced amount of active YAP, which is also a target of increased miR-21, causes decreased nuclear expression of YAP-mediated target genes. Since it is known that YAP has beneficial roles in promoting tissue repair and regeneration after injury so that its activation may be therapeutically useful, our results suggest that some components of Hippo pathway could become novel therapeutic targets for DMD treatment.

Role of YAP/TAZ in Cell Lineage Fate Determination and Related Signaling Pathways

“…In addition, myoblast differentiation into myotubes was inhibited by overexpression of mutant YAP that cannot be phosphorylated. The role of YAP deactivation in the further differentiation and maturation of myoblasts into myotubes was further validated by Vita et al (2018), who showed that the lack of skeletal muscle development and regeneration observed in Duchenne muscular dystrophy is associated with inactivation of the Hippo signaling pathway and increased YAP nuclear translocation.…”

Profiling of the muscle-specific dystroglycan interactome reveals the role of Hippo signaling in muscular dystrophy and age-dependent muscle atrophy

“…Yap/Yki together with TEAD/TEF transcription factors regulate the expression of genes that promote cell proliferation, prevent apoptosis, or control innate immunity [29][30][31]. Importantly in mammalian adult skeletal muscles, Yap has been shown to positively regulate skeletal muscle mass and protein synthesis following injury and upon neurogenic muscle atrophy [32] and have differential expression in healthy and dystrophic muscles [33,34]. Recent studies revealed the connection between the DGC and the Hippo pathway in the mouse heart; however, how this interaction influences Hippo and DGC signaling is not understood.…”

Circulating microRNAs Profile in Patients With Transthyretin Variant Amyloidosis

“…SCs samples were processed in lysis buffer (25 mM Tris/HCL, pH 7.4, 1.0 mM EGTA, 1.0 mM ethylen diamine tetraacetic acid (EDTA), protease, and phosphatase inhibitors) and total proteins concentration was determined using the Bio-Rad protein assay kit (Bio-Rad, Richmond, CA, United States). Integrated density values were expressed as a percentage of densitometric levels using arbitrary densitometric units (Vita et al, 2018).…”