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 2

DKO mice display MSM.

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DKO mice display MSM. (A) Immunohistochemistry of soleus muscle using an...
(A) Immunohistochemistry of soleus muscle using anti-laminin and anti-dystrophin antibodies. Dystrophin immunostaining was observed within myofibers only in DKO muscle. (B) Immunohistochemistry of soleus muscle using anti–β/slow MHC (red) and anti–pan-MHCII (green) antibodies. Inset shows a representative myofiber with subsarcolemmal β/slow MHC accumulation (arrows). (C) Immunoblotting of proteins from the soluble (left blot) and particulate (right blot) fractions of the soleus revealed an accumulation of β/slow MHC in DKO muscle. Anti-GAPDH was used as a control. (D) Electron microscopy of longitudinal (top left and bottom) and cross (top right and middle) sections of soleus muscle displayed accumulation of granular material and unassociated myosins in DKO myofibers. Arrows indicate mitochondria. Dotted lines indicate separation of inner myofiber core (below the line) from accumulating myosin (above the line). Middle panel shows an enlargement of the area within the box at top right. Arrowheads point toward abnormal Z-lines. Bottom: Z-line streaming found in skeletal muscle myopathies is seen in the top of this panel. M, M-line; N, nucleus. (E) NADH stain of soleus and tibialis anterior muscles shows disorganized mitochondria in DKO muscle. (F) Modified Gomori trichrome stain of soleus and tibialis anterior muscles shows no ragged red fiber myopathy. Scale bars: 100 μm (A and B); 2 μm (D, top left and bottom); 0.5 μm (D, top right and middle); 20 μm (E and F).