Regulation of Skeletal Muscle Development and Disease by an Actin-Dependent Transcriptional Circuit



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Congenital myopathies are a group of diseases that primarily affect skeletal muscle and cause muscle weakness that manifests at birth. With an incidence of 6 in 100,000 live births every year, myopathies are considered to be one of the top neuromuscular diseases in the world. Among congenital myopathies, nemaline myopathy (NM) is the most common variant. NM patients have generalized muscle weakness and lifelong disability, and its severest forms are neonatal lethal due to respiratory failure. Currently, there is no cure for NM, underscoring the necessity for new insights into the mechanisms of this severe disease. NM results from mutations in the actin thin filament proteins, and is associated with disorganization of myofibrils, reduced contractile force, and consequent failure to thrive. The main goal of my research has been to expand our knowledge of transcriptional networks that regulate sarcomeric actin, and to investigate how perturbations of these networks can lead to muscle disease. The expression of the actin gene, and the stability of the actin protein are tightly regulated during muscle development and maintenance. Myocardin-related transcription factors (MRTFs) play a central role in actin dynamics, by functioning as coactivators of the serum response factor (SRF), a master regulator of actin and other cytoskeletal genes. MRTFs additionally serve as sensors of actin polymerization and are sequestered in the cytoplasm by actin monomers. We explored the role of MRTFs in muscle development in vivo by generating mutant mice harboring a skeletal muscle-specific deletion of MRTF-B and a global deletion of MRTF-A and showed that the absence of MRTF-A and MRTF-B in the skeletal muscle leads to sarcomeric disarray and dramatic dysregulation of cytoskeletal genes. These findings highlight the importance of MRTFs in actin cycling and myofibrillogenesis. One of the cytoskeletal genes dysregulated in the MRTF dKO was Leiomodin-3 (Lmod3). This striated muscle-specific gene encodes for a putative actin nucleation factor and is downregulated in the MRTF dKO. Lmod3 is a component of the sarcomere thin filament, and its loss leads to compromised sarcomere integrity and nemaline myopathy (NM), a severe congenital muscle disease. We demonstrated an actin-dependent transcriptional circuit in which SRF cooperates with the myogenic transcription factor MEF2 to sustain the expression of the Lmod3 gene and other components of contractile apparatus. In turn, Lmod3 enhances MRTF-SRF activity by promoting actin polymerization. Together, these factors establish a regulatory loop to maintain skeletal muscle function. Finally, we investigated the Kelch protein family: a group of proteins that function as substrate-specific adaptors for Cullin RING E3 ligases; and are responsible for the balance between protein stability and degradation in many tissues, including striated muscle. Previously we have shown that KLHL40 is required for the stabilization of LMOD3. We further demonstrate that KLHL21, a muscle-enriched Kelch protein, operates in numerous unique pathways that potentially govern muscle and heart development, and the cell cycle. Future studies could pave the pathway to therapeutic approaches that improve heart and muscle regeneration, through our understanding of this gene and protein. Overall, our findings not only provide insight into how actin cycling networks regulate skeletal muscle specific transcripts and/or proteins to contribute to myogenesis, but also pave the way for potential new therapeutic approaches for congenital myopathies through the identification of disease-causing mutations.

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Pages i-xxvi are misnumbered as pages iii-xxviii.

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