The misfolded myosin response in health and disease

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Myopathies are inherited, progressive diseases of heart and skeletal muscle that often lead to severe physical impairment and premature death of affected patients. Frequently, mutations in constituents of the basic contractile apparatus of striated muscle, the sarcomere, were found to be causative for disease onset and progression. Although the composition of the sarcomere is well known, the molecular regulation of its assembly and the interplay of auxiliary proteins such as Unc45b or Hsp90a that guarantee sarcomerogenesis are still incompletely understood. Unc45b and Hsp90a are known to specifically function to regulate myosin folding. Interestingly, animal models carrying loss-of-function mutations in these two myosin chaperones display massively disorganized muscle structures, myofilament disassembly and a severely impaired motility, substantiating the importance of auxiliary and regulatory proteins in the assembly of structural components into fully functional sarcomeres and myofilaments.Very recently, the methyltransferase SET- and MYND-domain-containing protein 1 (Smyd1) was identified as an interaction partner of Unc45b and Hsp90a but also muscle Myosin, suggesting that Smyd1, similar to or even together with Unc45b or Hsp90a, to be involved in the regulation of myosin folding and assembly in vivo. Mutation of Unc45b, Hsp90a or Smyd1b leads to the accumulation of misfolded myosin, the subsequent induction of a complex gene program termed the misfolded myosin response (MMR) and finally the impairment of myofibril formation during development.In the proposed research we now aim (1) to dissect the role of defined Smyd1 mutations (identified during the first funding period) and (2) of loss of Smyd1 on adult muscle function and structure. Furthermore, we aim (3) to identify Smyd1-specific non-histone methylation targets and their biological role in sarcomerogenesis and the misfolded myosin response. In addition to our analyses in zebrafish, we will (4) define the role of Smyd1 loss and the impact of human Smyd1 variants on development and function in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Finally, we aim (5) to define and characterize factors, pathways and signaling networks (bioinformatics datasets) activated by the misfolded myosin response in vivo.In summary, the proposed research will ultimately help to further dissect the genetic and molecular underpinnings of sarcomere assembly and particularly myosin folding, which will be essential for the development of more specific strategies to treat diseases of striated muscle.