The myosin chaperone UNC-45 has an important role in maintaining the structure and function of muscle sarcomeres during adult aging

• Type of Material: Article
• Authors: Courtney J. Matheny, Emory University; Hiroshi Qadota, Emory University; Aaron O. Bailey, University of Texas, Galveston; Silvana Valdebenito-Silva, University of Texas, Galveston; Andres F. Oberhauser, University of Texas, Galveston; Guy M. Benian, Emory University
• Language: English
• Date: 2024-07-01
• Publisher: The American Society for Cell Biology
• Publication Version: Final Published Version
• Copyright Statement: © 2024 Matheny et al.
• License: Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International
• Final Published Version (URL): https://doi.org/10.1091/mbc.E23-12-0488
• Title of Journal or Parent Work: Molecular Biology of the Cell
• Volume: 35
• Issue: 7
• Start Page: ar98
• Grant/Funding Agency: Cancer Prevention Research Institute of Texas; Emory Initiative Biological Discovery Through Chemical Innovation; National Institutes of Health
• Grant/Funding Information: This work was supported in-part by National Institutes of Health grant R01GM118534 to G.M.B. and A.F.O., and also supported in-part by the Emory Initiative Biological Discovery Through Chemical Innovation (BDCI) to G.M.B. Many of the nematode strains used in this work were provided by the Caenorhabditis Genetics Center, which is funded by the National Institutes of Health Office of Research Infrastructure Programs (P40 OD010440). The Mass Spectrometry Facility at UTMB is supported in part by Cancer Prevention Research Institute of Texas (CPRIT) grant number RP190682. Monoclonal culture supernatants for five to six and five to eight antibodies were obtained from the University of Iowa Hybridoma Bank, and the five to six ascites fluids were kindly provided by Henry F. Epstein (deceased).
• Keywords: UNC-45; muscle organization; C. elegans; Sarcopenia
• Subject - Topics: Biology; Cells

Abstract

C. elegans undergo age-dependent declines in muscle organization and function, similar to human sarcopenia. The chaperone UNC-45 is required to fold myosin heads after translation and is likely used for refolding after thermally- or chemically-induced unfolding. UNC-45′s TPR region binds HSP-90 and its UCS domain binds myosin heads. We observe early onset sarcopenia when UNC-45 is reduced at the beginning of adulthood. There is sequential decline of HSP-90, UNC-45, and MHC B myosin. A mutation in age-1 delays sarcopenia and loss of HSP-90, UNC-45, and myosin. UNC-45 undergoes age-dependent phosphorylation, and mass spectrometry reveals phosphorylation of six serines and two threonines, seven of which occur in the UCS domain. Additional expression of UNC-45 results in maintenance of MHC B myosin and suppression of A-band disorganization in old animals. Our results suggest that increased expression or activity of UNC-45 might be a strategy for prevention or treatment of sarcopenia.