Striated Muscle Laminopathies
Determining how mutations in nuclear envelope proteins cause muscular dystrophy and dilated cardiomyopathy, with the goal to identify novel therapeutic approaches for these diseases.
Mutations in the LMNA gene cause numerous human diseases (‘laminopathies’) that include muscular dystrophy, dilated cardiomyopathy, and Hutchinson-Gilford progeria syndrome (HGPS). Although lamins A and C are expressed in almost all differentiated cells, the vast majority of mutations cause highly tissue-specific defects, primarily affecting skeletal and cardiac muscle and tendons. The molecular mechanisms responsible for these diseases remain incompletely understood, presenting a major hurdle in the development of effective treatments.
Current projects:
We are currently testing whether reducing mechanical stress on muscle nuclei or targeting DNA damage response pathways can reduce or prevent muscle diseases in vitro and in pre-clinical disease models of striated muscle laminopathies. Since it is likely that more than one mechanism contributes to the disease defects in laminopathies, we continue our research to identify the molecular disease drivers using in vivo models, primary myoblasts differentiated into mature muscle fibers, cardiac myocytes generated from patient-derived induced pluripotent stem cells, and engineered cardiac and skeletal muscle tissues.
Key findings:
We produced the first direct evidence that mutations associated with muscular laminopathies result in impaired nuclear structure and stability in vitro and in vivo by disrupting assembly of lamin A/C into filaments.
We showed that loss of lamin A/C and LMNA mutations linked to striated muscle disease result in impaired mechanotransduction in vitro and in vivo.
We demonstrated that LMNA mutations cause frequent nuclear envelope rupture, DNA damage, DNA damage response activation, and reduced cell viability in muscle cells in vitro and in vivo, and that reducing cytoskeletal forces on lamin A/C-deficient muscle cell nuclei prevents nuclear damage and improves muscle cell viability and function.
Representative publications:
Earle et al. Nat Mat 2020. Mutant lamins cause nuclear envelope rupture and DNA damage in skeletal muscle cells.
Maurer & Lammerding. Annu Rev Biomed Eng 2019. The Driving Force: Nuclear Mechanotransduction in Cellular Function, Fate, and Disease.
Dialynas et al. PLoS Genet 2015. Myopathic lamin mutations cause reductive stress and activate the Nrf2/Keap-1 pathway.
Zwerger et al. HumMolGen 2013. Myopathic lamin mutations impair nuclear stability in cells and tissue and disrupt nucleo-cytoskeletal coupling.
Ho et al. Nature 2013. Lamin A/C and emerin regulate MKL1-SRF activity by modulating actin dynamics.
Current project team members:
