DEFECTS IN MUSCLE DIFFERENTIATION AND MATURATION AS PATHOGENIC CONTRIBUTORS TO MUSCULAR DYSTROPHY CAUSED BY LAMIN A/C MUTATIONS

Abstract

Laminopathies, a broad class of diseases that primarily impact mechanically active tissues such as cardiac and skeletal muscle, are caused by genetic mutations in the LMNA gene, which encodes for the Lamin A/C protein. Lamins A/C form a dense protein network on the inside of the inner nuclear membrane and perform diverse roles in the cell, ranging from structural support of the nucleus to chromatin organization and transcriptional regulation. Many of the LMNA mutations result in Emery-Dreifuss muscular dystrophy, which presents with muscle weakness, muscle wasting, and cardiac conduction defects that lead to pre-mature death. To date, Emery-Dreifuss muscular dystrophy remains incurable, and the disease mechanism incompletely understood. In my doctoral work, I investigated three non-mutually exclusive hypotheses regarding the disease mechanism of Emery-Dreifuss muscular dystrophy: 1) disease causing LMNA mutations render the nuclear more susceptible to mechanical damage, resulting in cell death; 2) misregulation of myogenic differentiation leads to ineffective regeneration of muscle in response to injury; and 3) altered extracellular matrix structure and composition, possibly due to disturbed gene expression, leads to exacerbation of the phenotype through a positive mechanotransduction feedback loop. Using in vitro and in vivo models of Emery-Dreifuss muscular dystrophy, I found that the nuclear damage hypothesis is a major contributor to disease progression. Functional loss of lamins A/C resulted in increased nuclear fragility and nuclear envelope rupture, leading to DNA damage and activation of DNA damage response pathways. Additional defects in later stages of muscle development, including muscle fiber maturation and hypertrophy, may further contribute to disease phenotype. These insights provide important information on the impact of disease causing LMNA mutations and highlight DNA damage response pathways and muscle hypertrophy as key areas for potential treatment development.