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Science 294 (5547): 1704-1708

Copyright © 2001 by the American Association for the Advancement of Science

Identification of Ubiquitin Ligases Required for Skeletal Muscle Atrophy

Sue C. Bodine,1 Esther Latres,1 Susanne Baumhueter,2 Venus K.-M. Lai,1 Lorna Nunez,1 Brian A. Clarke,1 William T. Poueymirou,1 Frank J. Panaro,1 Erqian Na,1 Kumar Dharmarajan,1 Zhen-Qiang Pan,3 David M. Valenzuela,1 Thomas M. DeChiara,1 Trevor N. Stitt,1 George D. Yancopoulos,1 David J. Glass1*

Skeletal muscle adapts to decreases in activity and load by undergoing atrophy. To identify candidate molecular mediators of muscle atrophy, we performed transcript profiling. Although many genes were up-regulated in a single rat model of atrophy, only a small subset was universal in all atrophy models. Two of these genes encode ubiquitin ligases: Muscle RING Finger 1 (MuRF1), and a gene we designate Muscle Atrophy F-box (MAFbx), the latter being a member of the SCF family of E3 ubiquitin ligases. Overexpression of MAFbx in myotubes produced atrophy, whereas mice deficient in either MAFbx or MuRF1 were found to be resistant to atrophy. These proteins are potential drug targets for the treatment of muscle atrophy.

1 Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY, 10591-6707, USA.
2 Applied Biosystems, 850 Lincoln Center Drive, Foster City, CA 94404, USA.
3 Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, NY, 10029-6574, USA.
*   To whom correspondence should be addressed. E-mail: david.glass{at}regeneron.com

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   Abstract »    Full Text »    PDF »
Muscle atrophy; more than one string to MuRF1's bow?.
A. J. Murton (2011)
J. Physiol. 589, 4635
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Muscle sparing in muscle RING finger 1 null mice: response to synthetic glucocorticoids.
L. M. Baehr, J. D. Furlow, and S. C. Bodine (2011)
J. Physiol. 589, 4759-4776
   Abstract »    Full Text »    PDF »
Distinct protein degradation profiles are induced by different disuse models of skeletal muscle atrophy.
P. Bialek, C. Morris, J. Parkington, M. St. Andre, J. Owens, P. Yaworsky, H. Seeherman, and S. A. Jelinsky (2011)
Physiol Genomics 43, 1075-1086
   Abstract »    Full Text »    PDF »
Diaphragm muscle fiber function and structure in humans with hemidiaphragm paralysis.
W. N. Welvaart, M. A. Paul, H. W. H. van Hees, G. J. M. Stienen, J. W. M. Niessen, F. S. de Man, G. C. Sieck, A. Vonk-Noordegraaf, and C. A. C. Ottenheijm (2011)
Am J Physiol Lung Cell Mol Physiol 301, L228-L235
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Novel events in the molecular regulation of muscle mass in critically ill patients.
D. Constantin, J. McCullough, R. P. Mahajan, and P. L. Greenhaff (2011)
J. Physiol. 589, 3883-3895
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TRIM32 Protein Sensitizes Cells to Tumor Necrosis Factor (TNF{alpha})-induced Apoptosis via Its RING Domain-dependent E3 Ligase Activity against X-linked Inhibitor of Apoptosis (XIAP).
Y. S. Ryu, Y. Lee, K. W. Lee, C. Y. Hwang, J.-S. Maeng, J.-H. Kim, Y.-S. Seo, K.-H. You, B. Song, and K.-S. Kwon (2011)
J. Biol. Chem. 286, 25729-25738
   Abstract »    Full Text »    PDF »
Atrogin1/MAFbx: What Atrophy, Hypertrophy, and Cardiac Failure Have in Common.
D. Lee and A. Goldberg (2011)
Circ. Res. 109, 123-126
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Endogenous Muscle Atrophy F-Box Mediates Pressure Overload-Induced Cardiac Hypertrophy Through Regulation of Nuclear Factor-{kappa}B.
S. Usui, Y. Maejima, J. Pain, C. Hong, J. Cho, J. Y. Park, D. Zablocki, B. Tian, D. J. Glass, and J. Sadoshima (2011)
Circ. Res. 109, 161-171
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PKB signaling and atrogene expression in skeletal muscle of aged mice.
M. Gaugler, A. Brown, E. Merrell, M. DiSanto-Rose, J. A. Rathmacher, and T. H. Reynolds 4th (2011)
J Appl Physiol 111, 192-199
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Decreased specific force and power production of muscle fibers from myostatin-deficient mice are associated with a suppression of protein degradation.
C. L. Mendias, E. Kayupov, J. R. Bradley, S. V. Brooks, and D. R. Claflin (2011)
J Appl Physiol 111, 185-191
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Molecular characterization of skeletal muscle atrophy in the R6/2 mouse model of Huntington's disease.
P. She, Z. Zhang, D. Marchionini, W. C. Diaz, T. J. Jetton, S. R. Kimball, T. C. Vary, C. H. Lang, and C. J. Lynch (2011)
Am J Physiol Endocrinol Metab 301, E49-E61
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Muscle-specific expression of insulin-like growth factor 1 improves outcome in Lama2Dy-w mice, a model for congenital muscular dystrophy type 1A.
A. Kumar, J. Yamauchi, T. Girgenrath, and M. Girgenrath (2011)
Hum. Mol. Genet. 20, 2333-2343
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Dexamethasone alters the expression of genes related to the growth of skeletal muscle in chickens (Gallus gallus domesticus).
Z. G. Song, X. H. Zhang, L. X. Zhu, H. C. Jiao, and H. Lin (2011)
J. Mol. Endocrinol. 46, 217-225
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Upregulation of the CaV 1.1-ryanodine receptor complex in a rat model of critical illness myopathy.
S. D. Kraner, Q. Wang, K. R. Novak, D. Cheng, D. R. Cool, J. Peng, and M. M. Rich (2011)
Am J Physiol Regulatory Integrative Comp Physiol 300, R1384-R1391
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