Mechanically-induced nuclear damage and increased p53 signaling lead to myofiber dysfunction in skeletal muscle laminopathies


Ultra-Rare myopathies and dystrophies (<1:100,000 worldwide)

Poster Number: 237


Tyler Kirby, PhD, Ashley Earle, PhD, Gregory Fedorchak, PhD, Philipp Isermann, Jineet Patel, Sushruta Iruvanti, Steven Moore, MD, Gisèle Bonne, PhD, Lori Wallrath, PhD, Jan Lammerding, PhD


1. Cornell University, 2. Cornell University, 3. Cornell University, 5. Cornell University, 6. Cornell University, 7. The University of Iowa, 9. University of Iowa, 10. Cornell University

Mutations in the human LMNA gene, which encodes the nuclear envelope proteins lamins A and C, cause muscular dystrophy and other diseases collectively known as laminopathies. The molecular mechanisms responsible for these diseases remain incompletely understood, but the muscle-specific defects suggest that mutations may render nuclei more susceptible to mechanical stress. Using three mouse models of muscle laminopathies, we found that Lmna mutations caused extensive nuclear envelope damage, consisting of chromatin protrusions and transient rupture of the nuclear envelope, in skeletal muscle cells in vitro and in vivo. The nuclear envelope damage was associated with progressive DNA damage, activation of DNA damage response pathways, and reduced viability. Deletion of the key DNA damage response protein p53 in Lmna KO myofibers rescued cell viability, indicating that p53 is required for the cell death process. Intriguingly, in maturing skeletal muscle cells, nuclear envelope damage and DNA damage resulted from nuclear movement rather than actomyosin contractility, which were reversed by Kif5b depletion or LINC complex disruption. LINC complex disruption rescued myofiber function and viability, indicating that the myofiber dysfunction is the result of mechanically induced nuclear envelope damage. The extent of nuclear envelope damage and DNA damage in the different Lmna mouse models strongly correlated with the disease onset and severity in vivo, suggesting a crucial role of DNA damage in disease pathogenesis. Corroborating the mouse model data, muscle biopsies from patients with LMNA associated muscular dystrophy similarly revealed significant DNA damage compared to age-matched controls, particularly in severe cases of the disease. Taken together, these findings point to a new and important role of DNA damage as a pathogenic contributor for these skeletal muscle diseases.