Deciphering the role of Lmod2 in cardiac muscle and in dilated cardiomyopathy

Icahn School Of Medicine At Mount Sinai, New York NY

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Abstract

PROJECT SUMMARY Effective contractile force generation in muscle requires the proper assembly, regulation, and activation of actin-containing thin filaments. The long-term goal of our work is to decipher the mechanisms fundamental to the regulation of thin filament assembly and activation, and how perturbations in these processes lead to myopathies. Leiomodins (Lmods) are a family of actin- binding proteins that are critical for proper muscle function as mutations in all isoforms lead to development of muscle disease. Loss of function variants in LMOD2, which is the cardiac muscle- predominant isoform, cause severe infantile dilated cardiomyopathy (DCM). We previously discovered that Lmod2 functions to elongate thin filaments, and is essential for normal cardiac muscle function. In this current funding cycle, we found that Lmod2 impacts contractile activity independent of its role in thin filament length regulation. We also found that multiple pathogenic mutations result in loss of mutant LMOD2 protein expression due to nonsense-mediated mRNA decay, which can be restored using LMOD2-specific steric-blocking oligonucleotides. Finally, we have data revealing that serum response factor (SRF)-associated signalling is altered due to loss of, or mutations in Lmod2. We hypothesize that Lmod2 is a multifunctional protein that influences cardiac contractility through maintaining proper thin filament lengths and positively effecting activation of the thin filament. We propose a multidisciplinary approach utilizing a unique combination of in vitro assays, patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), and novel mouse models of human disease - together with several state-of-the-art approaches to accomplish three Specific Aims focused on determining: 1) the mechanisms underlying the thin filament length regulatory function(s) of Lmod2; 2) how Lmod2 influences contractility, independent of its role in regulating thin filament length and 3) how loss of, or mutations in, Lmod2 lead to DCM. Our integrative and comprehensive proposal will provide critical missing links in our understanding of pointed end actin dynamics and muscle function. We expect to identify signaling pathways that mediate Lmod2-linked disease progression and determine if they represent potential therapeutic targets. These studies will have a broad impact on understanding the etiology of a spectrum of diseases that result from mutations in thin filament pointed end proteins and shed light on the pathogenesis of DCM, regardless of its initial cause, as well as lay the groundwork for developing approaches to moderate disease progression.