During muscle atrophy, thick, but not thin, filament components are degraded by MuRF1-dependent ubiquitylation

By Shenhav Cohen, J. Brault, Steven P. Gygi, D. Glass, D. Valenzuela, C. Gartner, E. Latres, A. Goldberg. Journal of Cell Biology, 2009

617 citations recorded by the source corpus.

Loss of myofibrillar proteins is a hallmark of atrophying muscle. Expression of muscle RING-finger 1 (MuRF1), a ubiquitin ligase, is markedly induced during atrophy, and MuRF1 deletion attenuates muscle wasting. We generated mice expressing a Ring-deletion mutant MuRF1, which binds but cannot ubiquitylate substrates. Mass spectrometry of the bound proteins in denervated muscle identified many myofibrillar components. Upon denervation or fasting, atrophying muscles show a loss of myosin-binding protein C (MyBP-C) and myosin light chains 1 and 2 (MyLC1 and MyLC2) from the myofibril, before any measurable decrease in myosin heavy chain (MyHC). Their selective loss requires MuRF1. MyHC is protected from ubiquitylation in myofibrils by associated proteins, but eventually undergoes MuRF1-dependent degradation. In contrast, MuRF1 ubiquitylates MyBP-C, MyLC1, and MyLC2, even in myofibrils. Because these proteins stabilize the thick filament, their selective ubiquitylation may facilitate thick filament disassembly. However, the thin filament components decreased by a mechanism not requiring MuRF1.

Subfields: Cardiology and Cardiovascular Medicine, Cellular and Molecular Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/e3892ded2d4db0f824b292db56a91cf3d0b3789f

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Citations in the corpus

Cancer cachexia: mediators, signaling, and metabolic pathways. (2012, background): “This E3 ubiquitin ligase is responsible for mediating the ubiquitination of the thick filament of the sarcomere—MyHC (Clarke et al., 2007), and other thick filament components (Cohen et al., 2009).”
Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival. (2010, background): “FOXO3 by itself induces a set of atrophy-related genes, especially the muscle-specific ubiquitin ligases Atrogin-1 and MuRF1, which promotes breakdown of myofibrillar apparatus, and genes for autophagy (Cohen et al., 2009; Zhao et al., 2007).”
Glucocorticoid-induced skeletal muscle atrophy. (2013, background): “…al. / The International Journa een shown to function as a ligase for several regulatory proteins uch as MyoD and eIF3f, and MuRF-1 mainly for several myofibrilar proteins such as myosin heavy chain (MYHC), MyBP-C, MyLC1, yLC2, and actin (Clarke et al., 2007; Cohen et al., 2009; Polge et al., 011).”
Cellular and molecular mechanisms of muscle atrophy (2013, background): “, 2007), myosin binding protein C and myosin light chain (Cohen et al., 2009) (Fig.”
Mechanisms of IGF-1-Mediated Regulation of Skeletal Muscle Hypertrophy and Atrophy (2020, background): “In addition, by comparing the WT and transgenic mice expressing a RING deletion mutant of MuRF1, which binds but cannot ubiquitinate substrates, Cohen et al. found that atrophying muscles showed a loss of myosin-binding protein C (MyBP-C) and myosin light chains 1 and 2 (MyLC1 and MyLC2) from the my”
Fiber types in mammalian skeletal muscles. (2011, background): “The halflife of MyHCs may also change due to increased protein degradation: the E3 ubiquitin ligase MuRF1 is activated in atrophying muscle and is responsible for MyHC degradation (153, 161, 218); however, there is no evidence for isoform-specific accelerated degradation of MyHC in muscles undergoin”