FLNC Expression Level Influences the Activity of TEAD-YAP/TAZ Signaling

• Main Authors: Anastasia Knyazeva, Aleksandr Khudiakov, Raquel Vaz, Aleksey Muravyev, Ksenia Sukhareva, Thomas Sejersen, Anna Kostareva
• Format: Article
• Language: English
• Published: MDPI AG 2020-11-01
• Series: Genes
• Subjects: FLNC; genome editing; myogenic differentiation; Hippo signaling
• Online Access: https://www.mdpi.com/2073-4425/11/11/1343

Filamin C (FLNC), being one of the major actin-binding proteins, is involved in the maintenance of key muscle cell functions. Inherited skeletal muscle and cardiac disorders linked to genetic variants in <i>FLNC</i> have attracted attention because of their high clinical importance and possibility of genotype-phenotype correlations. To further expand on the role of FLNC in muscle cells, we focused on detailed alterations of muscle cell properties developed after the loss of FLNC. Using the CRISPR/Cas9 method we generated a C2C12 murine myoblast cell line with stably suppressed <i>Flnc</i> expression. FLNC-deficient myoblasts have a significantly higher proliferation rate combined with an impaired cell migration capacity. The suppression of <i>Flnc</i> expression leads to inability to complete myogenic differentiation, diminished expression of <i>Myh1</i> and <i>Myh4</i>, alteration of transcriptional dynamics of myogenic factors, such as <i>Mymk</i> and <i>Myog</i>, and deregulation of Hippo signaling pathway. Specifically, we identified elevated basal levels of Hippo activity in myoblasts with loss of FLNC, and ineffective reduction of Hippo signaling activity during myogenic differentiation. The latter was restored by <i>Flnc</i> overexpression. In summary, we confirmed the role of FLNC in muscle cell proliferation, migration and differentiation, and demonstrated for the first time the direct link between <i>Flnc</i> expression and activity of TEAD-YAP\TAZ signaling. These findings support a role of FLNC in regulation of essential muscle processes relying on mechanical as well as signaling mechanisms.