Myocardin-related transcription factors are required for skeletal muscle development

Abstract

Myocardin-related transcription factors (MRTFs) play a central role in the regulation of actin expression and cytoskeletal dynamics. Stimuli that promote actin polymerization allow for shuttling of MRTFs to the nucleus where they activate serum response factor (SRF), a regulator of actin and other cytoskeletal protein genes. SRF is an essential regulator of skeletal muscle differentiation and numerous components of the muscle sarcomere, but the potential involvement of MRTFs in skeletal muscle development has not been examined. We explored the role of MRTFs in muscle development in vivo by generating mutant mice harboring a skeletal muscle-specific deletion of MRTF-B and a global deletion of MRTF-A. These double knockout (dKO) mice were able to form sarcomeres during embryogenesis. However, the sarcomeres were abnormally small and disorganized, causing skeletal muscle hypoplasia and perinatal lethality. Transcriptome analysis demonstrated dramatic dysregulation of actin genes in MRTF dKO mice, highlighting the importance of MRTFs in actin cycling and myofibrillogenesis. MRTFs were also shown to be necessary for the survival of skeletal myoblasts and for the efficient formation of intact myotubes. Our findings reveal a central role for MRTFs in sarcomere formation during skeletal muscle development and point to the potential involvement of these transcriptional co-activators in skeletal myopathies.

Serum Response Factor Is Essential for Maintenance of Podocyte Structure and Function

“…Of note, Mkl1/ Mkl2 dKO mice, but not three-allele KO mice, showed somewhat lower expression of SRF in podocytes (Supplemental Figure 9); a similar reduction in Srf mRNA was seen in skeletal muscle lacking these cofactors. 24 IFM disclosed reduced expression of Synaptopodin and Podocin in glomeruli of Mkl1/Mkl2 dKO mice but not in Mkl2 KO or three-allele KOs, which were comparable with wildtype mice ( Figure 4C versus Figure 3B). The lifespan of Mkl1/Mkl2 dKO mice was over 10 weeks, slightly longer than Srf KO mice.…”

MRTFs‐ master regulators of EMT

“…The biological functions of MRTFs are multifaceted, and MRTFs are important regulators of developmental and normal physiological processes, and were also found to be implicated in several pathological conditions and diseases. MRTFs are required for skeletal muscle development regulating the normal organization of sarcomeres, the survival of myoblasts and the efficient formation of intact myotubes (Cenik et al, ). MRTF‐B was shown to be essential during smooth muscle differentiation (Oh et al, ), and smooth muscle cell‐specific transcription by certain RhoA‐dependent agonists was mediated by increased nuclear translocation of the MRTFs (Hinson et al, ).…”

MRTF-A promotes angiotensin II-induced inflammatory response and aortic dissection in mice

“…This may be due to the insufficient inhibition of MRTF-A by CCG-203971 during AD development. Alternatively, whole body Mrtfa deletion may developmentally alter the function of cells and tissue [44][45][46], which may affect AD pathogenesis. In addition, prevention of AD in the clinical situation is highly challenging.…”