Eliminating elevated p53 signaling fails to rescue skeletal muscle defects or extend survival in lamin A and C-deficient mice

Authors
Kirby, Tyler J., Zahr, Hind C., Fong, Ern Hwei Hannah, Lammerding, Jan


Lab

Journal
Cell Death Discovery

Abstract
Lamins A and C, encoded by the LMNA gene, are nuclear intermediate filaments that provide structural support to the nucleus and contribute to chromatin organization and transcriptional regulation. LMNA mutations cause muscular dystrophies, dilated cardiomyopathy, and other diseases. The mechanisms by which many LMNA mutations result in muscle-specific diseases have remained elusive, presenting a major hurdle in the development of effective treatments. Previous studies using striated muscle laminopathy mouse models found that cytoskeletal forces acting on mechanically fragile Lmna-mutant nuclei led to transient nuclear envelope rupture, extensive DNA damage, and activation of DNA damage response (DDR) pathways in skeletal muscle cells in vitro and in vivo. Furthermore, hearts of Lmna mutant mice have elevated activation of the tumor suppressor protein p53, a central regulator of DDR signaling. We hypothesized that elevated p53 activation could present a pathogenic mechanism in striated muscle laminopathies, and that eliminating p53 activation could improve muscle function and survival in laminopathy mouse models. Supporting a pathogenic function of p53 activation in muscle, stabilization of p53 was sufficient to reduce contractility and viability in wild-type muscle cells in vitro. Using three laminopathy models, we found that increased p53 activity in Lmna-mutant muscle cells primarily resulted from mechanically induced damage to the myonuclei, and not from altered transcriptional regulation due to loss of lamin A/C expression. However, global deletion of p53 in a severe muscle laminopathy model did not reduce the disease phenotype or increase survival, indicating that additional drivers of disease must contribute to the disease pathogenesis.

Keywords/Topics
eliminating;elevated;signaling;fails;rescue;skeletal;muscle;defects;extend;survival

BIOSEB Instruments Used:
Grip strength test (BIO-GS4)

Source :

https://www.nature.com/articles/s41420-024-01998-1

Produits associés

Test d'agrippement

DEMANDE DE PUBLICATION

Merci de votre intérêt pour notre gamme de produits et de votre demande pour cette publication qui vous sera envoyée si l'équipe de recherche et la revue le permettent. Notre équipe commerciale vous contactera dans les plus brefs délais.