title: Myosin accumulation and striated muscle myopathy result from the loss of muscle RING finger 1 and 3.
abstract: Maintenance of skeletal and cardiac muscle structure and function requires precise control of the synthesis, assembly, and turnover of contractile proteins of the sarcomere. Abnormalities in accumulation of sarcomere proteins are responsible for a variety of myopathies. However, the mechanisms that mediate turnover of these long-lived proteins remain poorly defined. We show that muscle RING finger 1 (MuRF1) and MuRF3 act as E3 ubiquitin ligases that cooperate with the E2 ubiquitin-conjugating enzymes UbcH5a, -b, and -c to mediate the degradation of beta/slow myosin heavy chain (beta/slow MHC) and MHCIIa via the ubiquitin proteasome system (UPS) in vivo and in vitro. Accordingly, mice deficient for MuRF1 and MuRF3 develop a skeletal muscle myopathy and hypertrophic cardiomyopathy characterized by subsarcolemmal MHC accumulation, myofiber fragmentation, and diminished muscle performance. These findings identify MuRF1 and MuRF3 as key E3 ubiquitin ligases for the UPS-dependent turnover of sarcomeric proteins and reveal a potential basis for myosin storage myopathies.
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9148, USA.
authors.forename: Jens
authors.initials: J
authors.lastname: Fielitz
authors.forename: Mi-Sung
authors.initials: MS
authors.lastname: Kim
authors.forename: John M
authors.initials: JM
authors.lastname: Shelton
authors.forename: Shuaib
authors.initials: S
authors.lastname: Latif
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Spencer
authors.forename: David J
authors.initials: DJ
authors.lastname: Glass
authors.forename: James A
authors.initials: JA
authors.lastname: Richardson
authors.forename: Rhonda
authors.initials: R
authors.lastname: Bassel-Duby
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
mesh_terms: D000818:Animals; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D006331:Heart Diseases / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009135:Muscular Diseases / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D009218:Myosins / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D025801:Ubiquitin / Q000378:metabolism; D000092468:Bromodomain Containing Proteins