Myosin accumulation and striated muscle myopathy result from the loss of muscle RING finger 1 and 3
Jens Fielitz, … , Rhonda Bassel-Duby, Eric N. Olson
Jens Fielitz, … , Rhonda Bassel-Duby, Eric N. Olson
Published September 4, 2007
Citation Information: J Clin Invest. 2007;117(9):2486-2495. https://doi.org/10.1172/JCI32827.
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Research Article Cardiology

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 β/slow myosin heavy chain (β/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

Jens Fielitz, Mi-Sung Kim, John M. Shelton, Shuaib Latif, Jeffrey A. Spencer, David J. Glass, James A. Richardson, Rhonda Bassel-Duby, Eric N. Olson

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Figure 1

DKO mice show a skeletal muscle myopathy.

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DKO mice show a skeletal muscle myopathy. (A) Mice at 12 weeks of age. (...
(A) Mice at 12 weeks of age. (B) H&E stain and (C) myosin ATPase activity of cross-sections from soleus and longitudinal sections from tibialis anterior muscles from 12-week-old WT and DKO mice. Subsarcolemmal eosinophilic material accumulated along the entire length of the myofiber around a central myofiber core of DKO muscle. Heterogeneity of fiber size, atrophic myofibers (arrowhead), and centrally localized nuclei (long arrow) were found in DKO muscle. Solid lines indicate outer myofiber membrane. Dotted lines define the central core, which is surrounded by accumulated material (asterisk). Short arrow indicates basophilic boundary surrounding inner fiber. Quantitation of myofiber cross-sectional area and determination of occupied surface area of myofibers from soleus muscle (n = 6 each). (D) Measurement of force development and fatigability. Representative recordings of force from soleus muscles. Quantitation of maximum force development from soleus and extensor digitorum longus (n = 6 each). mN, millinewtons. (E) Quantitation of skeletal muscle mass (n = 12 each) of 12-week-old mice. (F) Measurement of body weight with increasing age. Scale bars: 20 μm. #P < 0.01 versus WT and MuRF1–/–; *P < 0.01 versus MuRF3–/–; **P < 0.01 versus WT.